Substituted Pyrimidine Compound for Treating Cancer

ABSTRACT

The present invention discloses a substituted pyridine compound represented by formula I, and a pharmaceutically acceptable salt, stereoisomer and tautomer thereof. The compounds of the present invention are useful in the treatment of cancers.

The present application is a divisional application of U.S. patentapplication Ser. No. 16/067,158, 371c date Jun. 29, 2018, which is aNational Stage of PCT/CN2016/113887, filed Dec. 30, 2016, which claimspriority benefit of Chinese Patent Application No. CN201511028799.6,filed Dec. 31, 2015, Chinese Patent Application No. CN201610516637.5,filed Jul. 1, 2016, and Chinese Patent Application No. CN201610877404.8,filed Sep. 30, 2016. Each application is hereby incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a nitrogen-containing fusedheterocyclic compound, as well as a preparation method, an intermediate,a composition and a use thereof.

BACKGROUND OF THE INVENTION

Tumor is a type of cell cycle disease (CCD). Regulating or blocking thecell cycle is one of the ways to treat tumor. At present, many moleculesinvolved in the cell cycle regulation have been discovered, whereinCyclin-Dependent-Kinases (CDKs) are the core molecules in the cell cycleregulatory network. CDKs are catalytic subunits and are a family ofserine (Ser)/threonine (Thr) kinases, they function as important signaltransduction molecules in cells, form CDK-cyclin complexes with cyclinsand are involved in cell growth, proliferation, dormancy, or entry intoapoptosis. Cell cycle regulatory proteins play an important role in theregulation of cell proliferation. In the tumor cells, G1 cyclins and CDKdisorders are the most frequent variations in which many mechanisms areinvolved. These variations often cause tumorigenesis by activating tumorgenes and silencing tumor suppressor genes. Malignant cells affect theexpression of cell cycle regulatory proteins through genetic and growingmechanisms, causing overexpression of cyclins and expression loss of CDKinhibitors followed by incontrollable CDK activity.

Cell cycle checkpoints are the rate-limiting sites that control cellproliferation cycle, responsible for determining the integrity of DNAsynthesis, monitoring DNA replication, repairing DNA damage, andblocking entrance into mitosis period before DNA replication andmitosis, they precisely regulate the progression of cell cycle andprevent errors in the proliferation cycle. Cells respond to DNA damage,which activates the cell cycle checkpoints and cause cell cycle arrestto repair damaged DNA, or induce cell death by apoptosis or terminationof growth. Cell cycle arrest often occurs at the G1/S or G2/M junction,and the cell cycle checkpoint regulatory molecules are also new targetsfor antitumor drugs.

In the development of drugs, the first generation of CDK inhibitorsrepresented by flavopiridol, UCN-01 etc. are “pan-CDK” inhibitors, whichblocks all the subtypes of the CDK family in an equivalent manner,exhibits relatively high toxicity in clinical trials and some of themcannot reach the effective therapeutic dose. Therefore, people areinspired to develop selective CDK inhibitors, which are expected toimprove the selectivity of treatment and prevent normal cells fromdamages of side effects. In recent years, selective CDK inhibitors havebeen reported and entered clinical trials. Therefore, discovering highlyspecific and low-toxic cell cycle regulators is a frontier in theresearch of antitumor drugs.

CONTENT OF THE INVENTION

The technical problem to be solved in the present invention is toovercome the existing cell cycle regulators accompanied with severeclinical side effects due to low specificity, poor selectivity etc., orpoor activity in spite of high selectivity. Thus, the present inventionprovides a nitrogen-containing fused heterocyclic compound, as well as apreparation method, an intermediate, a composition and a use thereof,the compounds exhibit a high selectivity and a high inhibitory activitywith respect to CDK4 and CDK6 at a molecular level, an excellentinhibitory activity with respect to breast cancer cells at a cellularlevel, and significant inhibition of tumor cell proliferation associatedwith cyclin-dependent kinase activity at an animal level. The compoundsalso exhibits a good stability with respect to human or mouse livermicrosomes without significant inhibition of metabolic enzymes, good invivo absorption in mice and rats, a high bioavailability and gooddruggability.

The present invention provides a nitrogen-containing fused heterocycliccompound represented by formula (I), a pharmaceutically acceptable saltthereof, an enantiomer thereof, a diastereomer thereof, a tautomerthereof, a solvate thereof, an metabolite thereof or a drug precursorthereof;

wherein, p and q are independently 0 or 1;

m and n are independently 0, 1 or 2;

X and Y are independently CH or N;

the N atom in the cycle

is oxidized or non-oxidized;

preferably, at least one of p and q is 1 (for example, when p and q areboth 1, m is 0, 1 or 2, n is 0; or, when p and q are both 1, n is 0, 1or 2, m is 0; or, when p is 0, q is 1, m and n are independently 0, 1 or2; or, when p is 1, q is 0, m and n are independently 0, 1 or 2);

R¹ is hydrogen, hydroxy, cyano, thio, substituted or unsubstitutedC₂-C₂₀ alkenyl, substituted or unsubstituted C₂-C₂₀ alkynyl, halogen(e.g. fluorine), substituted or unsubstituted C₁-C₂₀ alkyl (e.g. methyl,trifluoromethyl), C₁-C₂₀ alkylthio, substituted or unsubstituted C₁-C₂₀alkoxy (e.g. methoxy), substituted or unsubstituted C₃-C₁₂ cycloalkyl(e.g. cyclopropyl), substituted or unsubstituted C₁-C₉ heterocycloalkyl,or “C₁-C₂₀ alkyl mono-substituted, di-substituted or unsubstitutedamino”; wherein, the two substituents in the “C₁-C₂₀ alkyldi-substituted amino” are the same or different;

R² is hydrogen, hydroxy, substituted or unsubstituted C₂-C₂₀ alkenyl,substituted or unsubstituted C₂-C₂₀ alkynyl, halogen, substituted orunsubstituted C₁-C₂₀ alkyl (e.g. methyl), substituted or unsubstitutedC₁-C₂₀ alkoxy (e.g. methoxy), substituted or unsubstituted C₁-C₂₀alkylthio (e.g. methylthio), substituted or unsubstituted C₃-C₁₂cycloalkyl (e.g. cyclopropyl), cyano, “C₁-C₂₀ alkyl mono-substituted,di-substituted or unsubstituted amino” or

wherein, the two substituents in the “C₁-C₂₀ alkyl di-substituted amino”are the same or different;

R³ is hydrogen, substituted or unsubstituted C₁-C₂₀ alkyl (e.g. methyl,ethyl, isopropyl, tert-butyl, 1-ethylpropyl, 1-cyclopropylethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,1-methyl-2,2,2-trifluoroethyl or cyclopropylmethyl), substituted orunsubstituted C₂-C₂₀ alkenyl, substituted or unsubstituted C₂-C₂₀alkynyl, substituted or unsubstituted C₃-C₁₂ cycloalkyl (e.g.1-methylcyclopropyl, cyclopropyl, 3-oxocyclobutyl 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3 -difluorocyclobutyl, cyclobutyl, cyclopentyl,cyclohexyl, or

or substituted or unsubstituted C₁-C₉ heterocycloalkyl (e.g. C₃-C₅heterocycloalkyl, preferably C₃ heterocycloalkyl; e.g. 3-oxetanyl,3-methyl-3-azacyclobutyl); wherein, the “heterocycloalkyl” connects toanother group via the carbon atom thereof, the heteroatom in theheterocycloalkyl is selected from the group consisting of O, N and S,the number of the heteroatom is 1 to 3, when the heteroatom is N, N canbe further substituted with C₁-C₃ alkyl, the heteroatom can be locatedat the para-position of the carbon atom that connects to another group(e.g. R³ is

the “substituted” in the “substituted or unsubstituted C₁-C₂₀ alkyl”,“substituted or unsubstituted C₂-C₂₀ alkenyl”, “substituted orunsubstituted C₂-C₂₀ alkynyl”, “substituted or unsubstituted C₁-C₂₀alkoxy”, “substituted or unsubstituted C₁-C₉ heterocycloalkyl”,“substituted or unsubstituted C₃-C₁₂ cycloalkyl” and “substituted orunsubstituted C₁-C₂₀ alkylthio” in the definitions of R¹, R² and R³refers to be independently substituted with the substituent selectedfrom the group consisting of halogen (e.g. fluorine, the number can be1, 2 or 3), hydroxyl, oxo (e.g. an oxo group attached to C₃, C₄ or C₅cycloalkyl, e.g.

thio, cyano, amino, nitro, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀ alkenyl,C₂-C₂₀ alkynyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₃-C₁₂ cycloalkyl (e.g.cyclopropyl) and “C₁-C₂₀ alkyl mono-substituted, di-substituted orunsubstituted amino”; wherein, the two substituents in the “C₁-C₂₀ alkyldi-substituted amino” are the same or different; when there are morethan one substituents, the substituents are the same or different;

R⁴ is hydrogen, halogen (e.g. fluorine), C₁-C₆ alkyl, C₁-C₃ alkoxy (e.g.methoxy), cyano or

R⁷ contained in R² and R⁴ is independently hydrogen, hydroxyl, C₁-C₆alkyl (e.g. methyl or ethyl), substituted or unsubstituted C₃-C₈cycloalkyl (e.g. cyclobutyl, cyclopropyl or 4-methylcyclohexyl), C₁-C₆alkoxy or “C₁-C₆ alkyl mono-substituted, di-substituted or unsubstitutedamino”; wherein, the “substituted” in the “substituted or unsubstitutedC₃-C₈ cycloalkyl” refers to be substituted by C₁-C₆ alkyl; the twosubstituents in the “C₁-C₆ alkyl di-substituted amino” are the same ordifferent;

at least one of R¹ and R⁴ is halogen;

R⁵ is hydrogen, substituted or unsubstituted C₁-C₂₀ alkyl (e.g.substituted or unsubstituted C₁-C₆ alkyl, preferably substituted orunsubstituted methyl, ethyl or propyl; e.g. substituted or unsubstitutedn-propyl or isopropyl; e.g. substituted or unsubstituted 2-methylpropyl;e.g. substituted or unsubstituted 1,2-dimethylpropyl; e.g.2-methoxyethyl, 2-hydroxyethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,dimethylaminomethyl or 2-dimethylamino-ethyl), substituted orunsubstituted C₂-C₂₀ alkenyl (e.g. vinyl), substituted or unsubstitutedC₂-C₂₀ alkynyl (e.g. ethynyl, 2-butynyl or 2-propynyl), substituted orunsubstituted C₃-C₁₂ cycloalkyl

substituted or unsubstituted C₁-C₉ heterocycloalkyl (e.g.tetrahydrogenpyrrolyl,

substituted or unsubstituted C heteroaryl, substituted or unsubstitutedC₃ -C₁₂ aryl,

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via thecarbon atom thereof;

in R⁵, each R⁸ is independently hydroxyl, substituted or unsubstitutedC₁-C₂₀ alkyl (the “substituted or unsubstituted C₁-C₂₀ alkyl” ispreferably “substituted or unsubstituted C₁-C₆ alkyl”, preferably“substituted or unsubstituted methyl or ethyl”; e.g.dimethylaminomethyl), substituted or unsubstituted C₂-C₂₀ alkenyl (e.g.vinyl), substituted or unsubstituted C₂-C₂₀ alkynyl (e.g. ethynyl),substituted or unsubstituted C₃-C₁₂ cycloalkyl, substituted orunsubstituted C₁-C₉ heteroaryl, substituted or unsubstituted C₃-C₁₂aryl, substituted or unsubstituted C₁-C₉ heterocycloalkyl (e.g.

substituted or unsubstituted C₁-C₂₀ alkoxy (e.g. methoxy or ethoxy) or

the “C₁-C₉ heterocycloalkyl” connects to another group via a carbon atomor a heteroatom thereof;

in R⁵, each R⁹ is independently hydrogen, hydroxyl, substituted orunsubstituted C₁-C₂₀ alkyl (e.g. methyl, ethyl, isopropyl, aminomethyl,hydroxymethyl, hydroxyethyl, methylaminomethyl, dimethylaminomethyl,2-dimethylamino-ethyl,

or methoxymethyl; the “C₁-C₂₀ alkyl” can be methyl, ethyl,

substituted or unsubstituted C₂-C₂₀ alkenyl (e.g. vinyl), substituted orunsubstituted C₂-C₂₀ alkynyl (e.g. ethynyl), substituted orunsubstituted C₃-C₁₂ cycloalkyl (e.g. cyclobutyl,

or 4-methylcyclohexyl), substituted or unsubstituted C₁-C₂₉ alkoxy (e.g.2-dimethylamino-ethoxy; the “C₁-C₂₀ alkoxy” can be methoxy or ethoxy),substituted or unsubstituted C₃-C₁₂ aryl, substituted or unsubstitutedC₁-C₉ heteroaryl, or substituted or unsubstituted C₁-C₉ heterocycloalkyl

the “C₁-C₉ heterocycloalkyl” connects to another group via a carbon atomor a heteroatom thereof;

in R⁸ and R⁹, each R^(10a) and R^(10b) is independently hydrogen,halogen, substituted or unsubstituted C₁-C₂₉ alkyl (e.g.2-dimethylamino-ethyl or 2-hydroxyethyl; wherein the “C₁-C₂₀ alkyl” canbe ethyl), substituted or unsubstituted C₂-C₂₀ alkenyl, substituted orunsubstituted C₂-C₂₀ alkynyl, substituted or unsubstituted C₃-C₁₂cycloalkyl, substituted or unsubstituted C₁-C₉ heteroaryl, substitutedor unsubstituted C₃-C₁₂ aryl, substituted or unsubstituted C₁-C₉heterocycloalkyl

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

the “substituted” in the “substituted or unsubstituted C₁-C₂₀ alkyl”,“substituted or unsubstituted C₂-C₂₀ alkenyl”, “substituted orunsubstituted C₂-C₂₀ alkynyl”, “substituted or unsubstituted C₃-C₁₂cycloalkyl”, “substituted or unsubstituted C₁-C₉ heterocycloalkyl”,“substituted or unsubstituted C₃-C₁₂ aryl”, “substituted orunsubstituted C₁-C₉ heteroaryl”, “substituted or unsubstituted C₁-C₂₀alkylthio” and “substituted or unsubstituted C₁-C₂₀ alkoxy” in thedefinitions of R⁵, R⁸, R⁹, R^(10a) and R^(10b) refers to beindependently substituted with the substituent selected from the groupconsisting of

C₁-C₂₀ alkyl (e.g. methyl, isopropyl), C₂-C₂₀ alkenyl (e.g. vinyl),C₂-C₂₀ alkynyl (e.g. 2-propynyl), hydroxy, nitro, carboxyl, formyl,thio, trifluoromethyl, C₁-C₂₀ silyl

wherein R^(si1), R^(si2), R^(si3) are each independently C₁-C₃ alkylsuch as methyl), halogen (e.g. fluorine, the number can be 1, 2 or 3),cyano, C₁-C₂₀ alkoxy (e.g. methoxy), C₃-C₁₂ cycloalkyl, substituted orunsubstituted C₁-C₉ saturated or unsaturated heterocycloalkyl (the“substituted” refers to be independently substituted with thesubstituent selected from the group consisting of methylene, oxo, thio,halogen, trifluoromethyl, hydroxy, —PO(OH)₂, —PO(OR^(ps))₂, C₁-C₂₀ alkylwhich is optionally substituted with propynyl, C₁-C₂₀ alkyl which isoptionally substituted with ethynyl, C₁-C₆ alkenyl, C₁-C₂₀ alkynyl,—B(OH)₂ and —B(OR^(bs))₂, wherein R^(ps) and R^(bs) are independentlyC₁-C₆ alkyl such as methyl, ethyl or propyl, the C₁-C₂₀ alkyl can beC₁-C₆ alkyl such as methyl, ethyl or propyl; unsaturatedheterocycloalkyl such as

saturated heterocycloalkyl such as

when there are more than one substituents, the substituents are the sameor different),

thioureido, C₃-C₁₂ aryl, C₁-C₉ heteroaryl,

-SeR¹⁹ and —SF₅; wherein heteroatom can be oxidized, N atom can bequatemized; wherein the “heterocycloalkyl” connects to another group viaa carbon atom or a heteroatom thereof; the N atom in

isoxidized or non-oxidized, when there are more than one substituents,the substituents are the same or different;

wherein, R^(11a) and R^(11b) are independently hydrogen, halogen,substituted or unsubstituted C₁-C₂₀ alkyl (e.g. substituted orunsubstituted C₁-C₆ alkyl, preferably substituted or unsubstituted C₁,C₂ or C₃ alkyl; e.g. —CF₃; e.g. hydroxyethyl, 2-dimethylaminoethyl),substituted or unsubstituted C₂-C₂₀ alkenyl (e.g. 2-propenyl),substituted or unsubstituted C₂-C₂₀ alkynyl (e.g. 2-propynyl),substituted or unsubstituted C₃-C₁₂ cycloalkyl, substituted orunsubstituted C₁-C₉ heterocycloalkyl

the substituent such as “C₁-C₂₀ alkyl”), guanidino, thioureido,substituted or unsubstituted C₃-C₁₂ aryl, substituted or unsubstitutedC₁-C₉ heteroaryl,

-SeR²⁶ or —SF₅; wherein the heteroatom can be oxidized, N atom can bequatemized; the “heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof; or, in

R^(11a) and R^(11b) together with the N atom attached form

wherein t and u are independently 1, 2 or 3, R^(c) is C(R^(cs))₂,NR^(cs), O, S, Si(R^(cs))₂ or Se, each R^(cs) is independently H, C₁-C₆alkyl (e.g. methyl, ethyl, propyl or isopropyl), or B(OH)₂; or, in

R^(11a) and R^(11b) together with the N atom attached form

wherein v and w are independently 1, 2 or 3, R^(ch) is CH or PH₂, R^(cx)is CH₂, O, S or ═N—OH, R^(cx) is preferably attached to R^(ch)

R^(hc) is H or C₁-C₆ alkyl (e.g. methyl, ethyl or propyl), preferablywhen R^(ch) is P, R^(hc) is C₁-C₆ alkyl; or in

R^(11a) and R^(11b) together with the N atom attached form

wherein v1 and w1 are independently 1, 2 or 3, R^(c1) and R^(c2) areindependently O, NH or N—CN;

wherein the “substituted” in the “substituted or unsubstituted C₁-C₂₀alkyl”, “substituted or unsubstituted C₂-C₂₀ alkenyl”, “substituted orunsubstituted C₂-C₂₀ alkynyl”, “substituted or unsubstituted C₃-C₁₂cycloalkyl”, “substituted or unsubstituted C₁-C₉ heterocycloalkyl”,“substituted or unsubstituted C₃-C₁₂ aryl” and “substituted orunsubstituted C₁-C₉ heteroaryl” in the definitions of R^(11a) andR^(11b) refers to be independently substituted with the substituentselected from the group consisting of C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl (e.g.vinyl), C₂-C₂₀ alkynyl (e.g. ethynyl), hydroxy, nitro, carboxyl, formyl,thio, C₁-C₂₀ silyl

wherein R^(si1), R^(si2), R^(si3) are each independently C₁-C₃ alkylsuch as methyl), halogen,

trifluoromethyl, cyano, C₁-C₂₀ alkoxy, C₃-C₁₂ cycloalkyl, C₁-C₉heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉ heteroaryl,

and —SF₅, when there are more than one substituents, the substituentsare the same or different; wherein the heteroatom can be oxidized, Natom can be quaternized; wherein the “heterocycloalkyl” connects toanother group via a carbon atom or a heteroatom thereof;

wherein each R¹² is independently hydrogen, halogen, C₁-C₂₀ alkyl (e.g.methyl), C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, hydroxy, —CF₃, —SF₅, C₁-C₂₀alkoxy (e.g. methoxy or ethoxy) or

wherein R¹³ is hydrogen, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀ alkenyl,C₂-C₂₀ alkynyl, hydroxy, —CF₃, —SF₅ or

wherein each R¹⁴ is independently halogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl,C₂-C₂₀ alkynyl, hydroxy, —CF₃, —SF₅, C₁-C₂₀ alkoxy or

wherein each R¹⁵, R^(16a) and R^(16b) is independently hydrogen,halogen, hydroxy, cyano, nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀alkylthio, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,

—CF₃, —SF₅, C₃-C₁₂ cycloalkyl, or “C₁-C₉ heterocycloalkyl which isoptionally substituted with C₁-C₂₀ alkyl”

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

wherein R^(17a) is independently hydrogen, halogen, hydroxy, cyano,nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₁-C₂₀ alkyl(e.g. methyl), C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, —CF₃, —SF₅, -SeR²⁶,

C₃-C₁₂ cycloalkyl or “C₁-C₉ heterocycloalkyl which is optionallysubstituted with C₁-C₂₀ alkyl”

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

wherein R^(17b) is independently hydrogen, halogen, hydroxy, cyano,nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl,C₂-C₂₀ alkynyl, —CF₃, —SF₅,

—OR²⁸, C₃-C₁₂ cycloalkyl or “C₁-C₉ heterocycloalkyl which is optionallysubstituted with C₁-C₂₀ alkyl”, wherein the “C₁-C₉ heterocycloalkyl”connects to another group via a carbon atom or a heteroatom thereof;

or, R^(17a) and R^(17b) together with the carbon atom, N atom

attached form substituted or unsubstituted C₁-C₉ heterocycloalkyl;wherein the “substituted” in the “substituted or unsubstituted C₁-C₉heterocycloalkyl” refers to be independently substituted with thesubstituent selected from the group consisting of C₁-C₂₀ alkyl, C₂-C₂₀alkenyl (e.g. vinyl), C₂-C₂₀ alkynyl (e.g. ethynyl), hydroxy, nitro,carboxyl, formyl, thio, C₁-C₂₀ silyl

wherein R^(si1), R^(si2), R^(si3) are each independently C₁-C₃ alkylsuch as methyl), halogen,

trifluoromethyl, cyano, C₁-C₂₀ alkoxy, C₃ -C₁₂ cycloalkyl, C₁-C₉heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉ heteroaryl,

and —SF₅, when there are more than one substituents, the substituentsare the same or different; wherein the “substituted or unsubstitutedC₁-C₉ heterocycloalkyl” connects to another group via a carbon atom or aheteroatom thereof;

wherein R^(18a) and R^(18b) are independently hydrogen, halogen,hydroxy, cyano, C₁-C₂₀ alkoxy, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, —CF₃, —SF₅, C₃ -C₁₂ cycloalkyl or “C₁-C₉ heterocycloalkyl whichis optionally substituted with C₁-C₂₀ alkyl”; wherein the “C₁-C₉heterocycloalkyl” connects to another group via a carbon atom or aheteroatom thereof;

or, R^(18a) and R^(18b) together with the heteroatom attached formsubstituted or unsubstituted C₁-C₉ heterocycloalkyl; wherein the“substituted” in the “substituted or unsubstituted C₁-C₉heterocycloalkyl” refers to be independently substituted with thesubstituent selected from the group consisting of C₁-C₂₉ alkyl, C₂-C₂₀alkenyl (e.g. vinyl), C₂-C₂₀ alkynyl (e.g. ethynyl), hydroxy, nitro,carboxyl, formyl, thio, C₁-C₂₀ silyl

wherein R^(si1), R^(si2), R^(si3) are each independently C₁-C₃ alkylsuch as methyl), halogen,

trifluoromethyl, cyano, C₁-C₂₀ alkoxy, C₃ -C₁₂ cycloalkyl, C₁-C₉heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉ heteroaryl,

and —SF₅, when there are more than one substituents, the substituentsare the same or different; wherein the “C₁-C₉ heterocycloalkyl” connectsto another group via a carbon atom or a heteroatom thereof;

wherein R¹⁹ is C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₃-C₁₂cycloalkyl, C₁-C₉ heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉ heteroaryl;

wherein the R²⁰ is independently hydrogen, halogen, C₁-C₂₀ alkyl, C₂-C₂₀alkenyl, C₂-C₂₀ alkynyl, hydroxy, —CF₃, —SF₅, C₃-C₅ heteroaryl (whereinthe number of heteroatom is 1 to 3, the heteroatom is O, N or S,

C₁-C₂₀ alkoxy or

wherein R²¹ in the definitions of R^(11a) and R^(11b) is independentlyhalogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, hydroxy, —CF₃,—SF₅, C₁-C₂₀ alkoxy or

wherein the R²², R^(23a) and R^(23b) are independently hydrogen,halogen, hydroxy, cyano, nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀alkylthio, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,

—CF₃, —SF₅, C₃-C₁₂ cycloalkyl, or “C₁-C₉ heterocycloalkyl which isoptionally substituted with C₁-C₂₀ alkyl”; wherein the “C₁-C₉heterocycloalkyl” connects to another group via a carbon atom or aheteroatom thereof;

wherein R^(24a) is independently hydrogen, halogen, hydroxy, cyano,nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₁-C₂₀ alkyl(e.g. methyl), C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, —CF₃, —SF₅,

-SeR³¹, C₃-C₁₂ cycloalkyl or “C₁-C₉ heterocycloalkyl which is optionallysubstituted with C₁-C₂₀ alkyl”; wherein the “C₁-C₉ heterocycloalkyl”connects to another group via a carbon atom or a heteroatom thereof;

wherein R^(24b) is independently hydrogen, halogen, hydroxy, cyano,nitro, amino, formyl, C₁-C₂₀ alkoxy, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀alkenyl, C₂-C₂₀ alkynyl, —CF₃, —SF₅,

—OR³², C₃-C₁₂ cycloalkyl or “C₁-C₉ heterocycloalkyl which is optionallysubstituted with C₁-C₂₀ alkyl”

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

or, R^(24a) and R^(24b) together with the carbon atom, N atom attachedform substituted or unsubstituted C₁-C₉ heterocycloalkyl; wherein the“substituted” in the “substituted or unsubstituted C₁-C₉heterocycloalkyl” refers to be independently substituted with thesubstituent selected from the group consisting of halogen, hydroxy,cyano, nitro, amino, formyl, carboxyl, thio, C₁-C₂₀ silyl, C₁-C₂₀alkoxy, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀ alkenyl (e.g. vinyl), C₂-C₂₀alkynyl (e.g. ethynyl), —CF₃, —SF₅,

C₃ -C12 cycloalkyl, C₁-C₉ heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉heteroaryl,

-SeR³¹, “C₁-C₂₀ alkyl mono-substituted, di-substituted or unsubstitutedamino” and —SF₅, when there are more than one substituents, thesubstituents are the same or different; wherein the “substituted orunsubstituted C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

wherein the R^(25a) and R^(25b) are independently hydrogen, halogen,hydroxy, cyano, C₁-C₂₀ alkoxy(e.g. ethoxy), C₁-C₂₀ alkyl(e.g. methyl),C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, —CF₃, —SF₅, C₃-C₁₂ cycloalkyl or “C₁-C₉heterocycloalkyl which is optionally substituted with C₁-C₂₀ alkyl”

wherein the “C₁-C₉ heterocycloalkyl” connects to another group via acarbon atom or a heteroatom thereof;

or, R^(25a) and R^(25b) together with the heteroatom attached formsubstituted or unsubstituted C₁-C₉ heterocycloalkyl; wherein the“substituted” in the “substituted or unsubstituted C₁-C₉heterocycloalkyl” refers to be independently substituted with thesubstituent selected from the group consisting of halogen, hydroxy,cyano, nitro, amino, formyl, carboxyl, thio, C₁-C₂₀ silyl, C₁-C₂₀alkoxy, C₁-C₂₀ alkyl (e.g. methyl), C₂-C₂₀ alkenyl (e.g. vinyl), C₂-C₂₀alkynyl (e.g. ethynyl), —CF₃, —SF₅,

C₃ -C₁₂ cycloalkyl, C₁-C₉ heterocycloalkyl, C₃-C₁₂ aryl, C₁-C₉heteroaryl,

-SeR³¹, “C₁-C₂₀ alkyl mono-substituted, di-substituted or unsubstitutedamino” and —SF₅, when there are more than one substituents, thesubstituents are the same or different; wherein the “C₁-C₉heterocycloalkyl” connects to another group via a carbon atom or aheteroatom thereof;

wherein R²⁶ is independently C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₃-C₁₂ cycloalkyl, C₁-C₉ heterocycloalkyl, C₃-C₁₂ aryl or C₁-C₉heteroaryl;

wherein R^(27a) and R^(27b) are independently hydrogen, halogen,hydroxy, cyano, formyl, C₁-C₂₀ alkoxy, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,—CF₃, —SF₅, C₃-C₁₂ cycloalkyl, substituted or unsubstituted C₁-C₉heterocycloalkyl

or substituted or unsubstituted C₁-C₂₀ alkyl(e.g. C₁-C₆ alkyl,preferably methyl, ethyl or propyl); wherein the “substituted” in the“substituted or unsubstituted C₁-C₂₀ alkyl” and “substituted orunsubstituted C₁-C₉ heterocycloalkyl” refers to be independentlysubstituted with the substituent selected from the group consisting ofhalogen, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio and C₁-C₂₀ silyl, when thereare more than one substituents, the substituents are the same ordifferent; wherein the “C₁-C₉ heterocycloalkyl” connects to anothergroup via a carbon atom or a heteroatom thereof;

wherein R²⁸ is independently C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, or substituted or unsubstituted C₁-C₂₀ silyl; wherein thesubstituent in the “substituted or unsubstituted C₁-C₂₀ silyl” is C₂-C₂₀alkenyl or C₂-C₂₀ alkynyl;

wherein R^(29a) and R^(29b) are independently hydrogen, halogen,hydroxy, cyano, formyl, C₁-C₂₀ alkoxy, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,—CF₃, —SF₅, C₃-C₁₂ cycloalkyl, substituted or unsubstituted C₁-C₉heterocycloalkyl

or substituted or unsubstituted C₁-C₂₀ alkyl; wherein the “substituted”in the “substituted or unsubstituted C₁-C₂₀ alkyl” and “substituted orunsubstituted C₁-C₉ heterocycloalkyl” refers to be independentlysubstituted with the substituent selected from the group consisting ofhalogen, C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio and C₁-C₂₀ silyl, when thereare more than one substituents, the substituents are the same ordifferent; wherein the “C₁-C₉ heterocycloalkyl” connects to anothergroup via a carbon atom thereof;

wherein R³⁰ is independently hydrogen, hydroxy, C₁-C₂₀ alkyl which isoptionally substituted with halogen, or C₁-C₂₀ alkyl mono-substituted,di-substituted or unsubstituted amino;

wherein R³¹ is independently hydrogen, cyano, nitro, hydroxy, C₁-C₂₀alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₃-C₁₂ cycloalkyl, C₁-C₉heterocycloalkyl, C₆-C₁₂ aryl, or C₁-C₉ heteroaryl;

wherein R³² is independently C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, or substituted or unsubstituted C₁-C₂₀ silyl; wherein thesubstituent in the “substituted or unsubstituted C₁-C₂₀ silyl” is C₂-C₂₀alkenyl or C₂-C₂₀ alkynyl;

wherein each of R^(33a) and R^(33b) is independently hydrogen, hydroxy,cyano, nitro, halogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,alkoxy, C₃-C₁₂ cycloalkyl, C₁-C₉ heterocycloalkyl, C₆-C₁₂ aryl, or C₁-C₉heteroaryl;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently hydrogen, hydroxy,C₁-C₂₀ alkyl, C₃-C₁₂ cycloalkyl or C₃-C₁₂ heterocycloalkyl, but R^(6a)and R^(6b) are not hydroxy at the same time, R^(6c) and R^(6d) are nothydroxyl at the same time; or R^(6a) and R^(6b) together with the carbonatom attached form carbonyl; or R^(6c) and R^(6d) together with thecarbon atom attached form carbonyl;

the number of the heteroatom in the “heterocycloalkyl”, “heteroaryl” is1 to 7 selected from the group consisting of oxygen, nitrogen,phosphorus, sulfur, selenium, boron and silicon;

and, the compound I is not selected from the group consisting of

Preferably, the C₂-C₂₀ alkenyl contained in the term “substituted orunsubstituted C₂-C₂₀ alkenyl” and the term “C₂-C₂₀ alkenyl” isindependently C₂-C₁₂ alkenyl; more preferably, the C₂-C₂₀ alkenylcontained in the term “substituted or unsubstituted C₂-C₂₀ alkenyl” isindependently C₂-C₆ alkenyl.

Preferably, the C₂-C₂₀ alkynyl contained in the term “substituted orunsubstituted C₂-C₂₀ alkynyl” and the term “C₂-C₂₀ alkynyl” isindependently C₂-C₁₂ alkynyl; more preferably, C₂-C₂₀ alkynyl containedin the term “substituted or unsubstituted C₂-C₂₀ alkynyl” isindependently C₂-C₆ alkynyl.

Preferably, the C₁-C₂₀ alkyl contained in the term “substituted orunsubstituted C₁-C₂₀ alkyl”, “C₁-C₂₀ alkyl” and “C₁-C₂₀ alkylmono-substituted, di-substituted or unsubstituted amino”is independentlyC₁-C₁₂ alkyl; more preferably, the C₂-C₂₀ alkyl contained in the term“substituted or unsubstituted C₁-C₂₀ alkyl” is independently C₁-C₆alkyl; most preferably, the C₂-C₂₀ alkyl contained in the term“substituted or unsubstituted C₁-C₂₀ alkyl” is independently C₁-C₃alkyl.

Preferably, the C₁-C₂₀ alkylthio contained in the term “substituted orunsubstituted C₁-C₂₀ alkylthio” and “C₁-C₂₀ alkylthio” is independentlyC₁-C₁₂ alkylthio; more preferably, the C₂-C₂₀ alkylthio contained in theterm “substituted or unsubstituted C₁-C₂₀ alkylthio” is independentlyC₁-C₆ alkylthio; most preferably, the C₂-C₂₀ alkylthio contained in theterm “substituted or unsubstituted C₁-C₂₀ alkylthio” is independentlyC₁-C₃ alkylthio.

Preferably, the C₁-C₂₀ alkoxy contained in the term “substituted orunsubstituted C₁-C₂₀ alkoxy” and the term “C₁-C₂₀ alkoxy” isindependently C₁-C₁₂ alkoxy; more preferably, the C₁-C₂₀ alkoxycontained in the term “substituted or unsubstituted C₁-C₂₀ alkoxy” isindependently C₁-C₆ alkoxy; most preferably, the C₁-C₂₀ alkoxy containedin the term “substituted or unsubstituted C₁-C₂₀ alkoxy” isindependently C₁-C₃ alkoxy.

Preferably, the “C₁-C₂₀ silyl” is independently “C₁-C₁₂ silyl”; morepreferably, the “C₁-C₂₀ silyl” is independently “C₁-C₆ silyl”; mostpreferably, the “C₁-C₂₀ silyl”is independently “C₁-C₃ silyl”.

Preferably, the C₃-C₁₂ cycloalkyl contained in the term “substituted orunsubstituted C₃-C₁₂ cycloalkyl” is independently C₃-C₈ cycloalkyl; morepreferably, the C₃-C₁₂ cycloalkyl contained in the term “substituted orunsubstituted C₃-C₁₂ cycloalkyl” is independently C₃-C₆ cycloalkyl.

Preferably, the C₁-C₉ heterocycloalkyl contained in the term“substituted or unsubstituted C₁-C₉ heterocycloalkyl” is independentlyC₃-C₈ heterocycloalkyl having 1 to 4 (e.g. 1 to 3) heteroatom selectedfrom the group consisting of boron, silicon, oxygen, sulfur, selenium,nitrogen and phosphorus; more preferably, the C₁-C₉ heterocycloalkylcontained in the term “substituted or unsubstituted C₁-C₉heterocycloalkyl” is independently C₃-C₅ heterocycloalkyl having 1 to 4(e.g. 1 to 3) heteroatom selected from the group consisting of boron,silicon, oxygen, sulfur, selenium, nitrogen and phosphorus.

Preferably, the C₁-C₉ heteroaryl contained in the term “substituted orunsubstituted C₁-C₉ heteroaryl” is independently C₁-C₆ heteroaryl; morepreferably, the C₁-C₉ heteroaryl contained in the term “substituted orunsubstituted C₁-C₉ heteroaryl” is independently C₁-C₆ heteroaryl having1 to 4 heteroatom selected from the group consisting of boron, silicon,oxygen, sulfur, selenium, nitrogen and phosphorus.

Preferably, the C₃-C₁₂ aryl contained in the term “substituted orunsubstituted C₃-C₁₂ aryl” is independently C₆-C₁₀ aryl.

In some embodiments, the definitions are preferably as follows:

In the compound I, preferably, p is 1,q is 1,m is 0 or 1,n is 0.

In the compound I, preferably, X is N.

In the compound I, preferably, R¹ is halogen or trifluoromethyl.

In the compound I, preferably, R² is C₁-C₆ alkyl.

In the compound I, preferably, R³ is substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈ cycloalkyl.

In the compound I, preferably, R⁴ is halogen.

In the compound I, preferably, R⁵ is hydrogen, substituted orunsubstituted C₁-C₆ alkyl,

In the compound I, preferably, R⁸ is independently substituted orunsubstituted C₁-C₆ alkyl, or C₁-C₆ alkoxy.

In the compound I, preferably, R⁹ is vinyl, substituted or unsubstitutedC₁-C₆ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted heterocycloalkyl having 3 to 8 carbon atoms and 1 to 4heteroatom selected from the group consisting of oxygen, sulfur andnitrogen, substituted or unsubstituted C₁-C₆ alkoxy or

In the compound I, preferably, R^(10a) a and R^(10b) are independentlyhydrogen, or substituted or unsubstituted C₁-C₆ alkyl.

In the compound I, preferably, the “substituted” in the “substituted orunsubstituted C₁-C₂₀ alkyl”, “substituted or unsubstituted C₃-C₁₂cycloalkyl”, “substituted or unsubstituted C₁-C₉ heterocycloalkyl” and“substituted or unsubstituted C₁-C₂₀ alkoxy” in the definitions of R⁵,R⁸, R⁹, R^(10a) and R^(10b) refers to be independently substituted withthe substituent selected from the group consisting of

hydroxy, halogen, C₁-C₃ alkoxy, “substituted or unsubstituted C₁-C₉saturated or unsaturated heterocycloalkyl” and

when there are more than one substituents, the substituents are the sameor different.

In the compound I, preferably, R^(11a) and R^(11b) are independentlyhydrogen, or C₁-C₆ alkyl.

In the compound I, preferably, R¹² is hydroxy, C₁-C₆ alkoxy or

In the compound I, preferably, R^(27a) and R^(27b) are independentlyC₁-C₆ alkyl.

In the compound I, preferably, R^(6a), R^(6b) R^(6c) and R^(6d) areindependently hydrogen; or R^(6c) and R^(6d) together with the carbonatom attached form carbonyl.

In some embodiments, the definitions are preferably as follows:

p is preferably 1.

q is preferably 1.

n is preferably 0.

m is preferably 1.

X is preferably N.

Y is preferably CH.

N atom in the cycle

is preferably oxidized or non-oxidized;

R^(6a), R^(6b), R^(6c) and R^(6d) are preferably hydrogen.

R¹ is preferably halogen (e.g. fluorine).

R² is preferably C₁-C₆ alkyl.

R³ is preferably substituted or unsubstituted C₁-C₂₀ alkyl (e.g.isopropyl or tert-butyl), or substituted or unsubstituted C₃-C₁₂cycloalkyl (e.g. 1-methylcyclopropyl or cyclopropyl).

R⁴ is preferably halogen (e.g. fluorine).

R⁵ is preferably substituted C₁-C₂₀ alkyl (e.g. substituted ethyl; e.g.substitute disopropyl).

The “substituted” in the “substituted C₁-C₂₀ alkyl” in the definition ofR⁵ refers to preferably be substituted with the substituent selectedfrom the group consisting of substituted or unsubstituted C₁-C₉saturated or unsaturated heterocycloalkyl,

when there are more than one substituents, the substituents are the sameor different; N atom in

is oxidized or non-oxidized.

Preferably, R^(11a) and R^(11b) are independently hydrogen, substitutedor unsubstituted C₁-C₂₀ alkyl(e.g. substituted or unsubstituted C₁-C₆alkyl, preferably substituted or unsubstituted C₁, C₂ or C₃ alkyl; e.g.—CF₃; e.g. hydroxyethyl, 2-dimethylaminoethyl), or

R^(11a) and R^(11b) together with the N atom attached form

wherein t and u are independently 1, 2 or 3, R^(c) is C(R^(cs))₂,NR^(cs), O, S, Si(R^(cs))₂ or Se, each R^(cs) is independently H, C₁-C₆alkyl (e.g. methyl, ethyl, propyl or isopropyl), or B(OH)₂; or in

R^(11a) and R^(11b) together with the N atom attached form

wherein v and w are independently 1, 2 or 3, R^(ch) is CH or PH₂, R^(cx)is CH₂, O, S or ═N—OH, R^(cx) is preferably attached to R^(ch)

R^(hc) is H or C₁-C₆ alkyl (e.g. methyl, ethyl or propyl), preferablywhen R^(ch) is P, R^(hc) is C₁-C₆ alkyl.

Preferably, R¹⁵ is C₁-C₆ alkyl.

Preferably, the “substituted” in the term “substituted or unsubstitutedC₁-C₂₀ alkyl” in the definitions of R^(11a) and R^(11b) refers to beindependently substituted with the substituent selected from the groupconsisting of hydroxy, C i-C₆ silyl,

when there are more than one substituents, the substituents are the sameor different.

R^(24a) is preferably hydrogen.

R^(24b) is preferably C₁-C₆ alkyl.

Preferably, R^(25a) and R^(25b) are independently hydroxyl or C₁-C₆alkoxy (e.g. ethoxy).

Preferably, R^(27a) and R^(27b) are independently C₁-C₆ alkyl.

Preferably, the compound I in the present invention is selected from thegroup consisting of

The nitrogen-containing fused heterocyclic compounds involved in thepresent invention may exhibit tautomerism, structural isomerism andstereoisomerism. The present invention includes any tautomeric orstructural isomeric or stereoisomeric forms thereof and mixturesthereof, which have high selectivity and high inhibitory activity onCDK4 and CDK6, at the same time, they have better inhibitory activityagainst breast cancer cells, which is not limited to any of the isomersor the mixture thereof.

The nitrogen-containing fused heterocyclic compounds in the presentinvention can be prepared by various methods well-known to those skilledin the field of organic synthesis and medicinal chemistry, or preparedby the methods described below combined with the synthetic methods knownin the field of organic chemistry or transformational methods thereofunderstood by those skilled in the art.

The preparation method for the nitrogen-containing fused heterocycliccompounds can start from readily available starting materials using thefollowing general methods and processes to prepare the compound in thepresent invention. It will be understood that where typical orpreferable process operating conditions (e.g. reaction temperature,time, mole ratio of reactants, solvent, pressure, etc.) are given; otherprocess operating conditions can also be used, unless otherwisespecified. Optimum reaction conditions may vary with the specificreactant or solvent used, but these conditions can be determined bythose skilled in the art by routine optimization procedures.

The preparation method for the nitrogen-containing fused heterocycliccompounds described herein can be monitored by any suitable method knownin the art. For example, the product formation can be monitored bynuclear magnetic resonance, infrared spectroscopy, spectrophotometry ormass spectrometry, HPLC, or thin layer chromatography.

The preparation method for the nitrogen-containing fused heterocycliccompound may involve protection and deprotection of multiple chemicalgroups. The need for protection and deprotection, as well as the choiceof the appropriate protecting group, can be easily determined by thoseskilled in the art. The chemical process of the protecting group canrefer to Greene et al., Protective Groups in Organic Synthesis, SecondEdition, Wiley & Sons, 1991, which is incorporated herein by referencein its entirety.

The preparation method described herein can be carried out in a suitablesolvent, which can be readily selectable by those skilled in the art oforganic synthesis. A suitable solvent does not substantially react withthe starting materials, intermediates or products at the temperature atwhich the described reaction is carried out. The temperature at whichthe reaction is carried out may vary from the solvent's freezing pointto the solvent's boiling temperature. The reaction can be carried out ina solvent or a mixture of multiple solvents. Depending on a specificreaction step, the solvent suitable for the specific reaction step canbe selected.

On this basis, particularly preferably (but not limited to reagents andsolvents in the reaction condition), the present invention furtherprovides a preparation method for the nitrogen-containing fusedheterocyclic compound, which is any one of the following methods:

method 1:

when R⁵ is hydrogen, the preparation method for the compound representedby formula I comprises conducting Suzuki coupling reaction to give 1C,followed by conducting Buchwald coupling with the compound representedby formula 1C and

to remove the protecting group and give the compound represented byformula I; the PG in the compound represented by formula 1D is aprotecting group;

wherein X, Y, m, n, p, q, R¹, R², R³, R⁴, R^(6a), R^(6b), R^(6c) andR^(6d) are defined as above;

the PG in the compound represented by formula 1D can be variousconventional amino protecting groups in the art, preferably Boc, for thepurpose of making certain reactive groups (e g amino group) notparticipate in the reaction when

reacts with compound 1C;

the condition of the deprotection reaction can be conventional removalconditions for various protecting groups in the art, e.g. conditions ofhydrolysis reaction, conditions of amine hydrolysis reaction, conditionsof hydrogenation reaction, and the like;

after the completion of deprotection reaction, preferably furthercomprising post-treatment; the method and condition of thepost-treatment can be conventional methods and conditions forpost-reaction treatment in the art, preferably comprising washing thereaction system, drying, filtering, evaporating to dryness; thenconducting column chromatography; or, the reaction system is distilledto remove the solvent, washed, filtered; or, the reaction system isdistilled to remove the solvent, subjected to thin layer chromatography;

the condition of the substitution reaction or the transition metalcatalyzed coupling reaction can be various conventional conditions ofsuch reactions in the art; the substitution reaction may be carried outby heating or pressurizing or acid-base catalyzing etc.;

wherein, the condition of each reaction step in the reaction route canbe carried out according to conventional conditions of such reactions inthe art;

method 2:

when R⁵ is hydrogen, a preparation method for the compound representedby formula I comprises subjecting the 1C obtained according to method 1to ammonolysis reaction, then reacting with

to give 2A, followed by removing the protecting group to give thecompound represented by formula I;

wherein X, Y, m, n, p, q, R¹, R², R³, R⁴, R^(6a), R^(6b), R^(6c) andR^(6d) are defined as above;

method 3:

when R⁵ is

and R¹¹ is substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted C₃-C₈ cycloalkyl, the preparation method for the compoundrepresented by formula I comprises that in organic solvent (e.g.selected from the group consisting of 1,4-dioxane, dichloromethane andDMF), in the presence of a condensing agent (e.g. HOBt and EDCI),conducting condensation reaction with compound 3A and

to give compound I; the condition of the condensation reaction can beconventional conditions in the art;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R¹¹, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

method 4:

when R⁵ is

the preparation method for the compound represented by formula Icomprises that in organic solvent (e.g. tetrahydrofuran), in thepresence of the base (e.g. pyridine), reacting compound 4A with

to give compound 4B, followed by conducting hydrolysis reaction to givecompound I; the conditions of the amide reaction and the hydrolysisreaction can be conventional conditions in the art;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R^(6a), R^(6b), R^(6c), R^(6d) and R⁸are defined as above;

method 5:

when R⁵ is

R¹¹ is substituted C₁-C₆ alkyl or C₃-C₈ cycloalkyl, and the substituentis

when R^(13b) is H, the preparation method for the compound representedby formula I comprises that in organic solvent (e.g. selected from thegroup consisting of 1,4-dioxane, dichloromethane and DMF), in thepresence of condensing agent (e.g. HOBt and EDCI), reacting compound 5Awith

to give compound 5B, then removing the protecting group of the aminogroup to give compound I; the condition of the amide reaction and thedeprotection reaction can be conventional conditions in the art;R^(13a)NH—(CH₂)_(n1)—C(═O)— is R⁵; —(CH₂)_(n1)— is the substituted C₁-C₆alkyl or C₃-C₈ cycloalkyl;

X, Y, m, n, p, q, R¹, R², R³, R⁴, ₁, R^(6a), R^(6b), R^(6c), R^(6d) andR^(13a) are defined as above;

PG in the compound represented by formula 5B can be various conventionalamino protecting groups in the art, preferably Boc, for the purpose ofmaking certain reactive groups (e.g. amino group) not participate in thereaction when

reacts with compound 5A;

method 6:

when R⁵ is

R¹¹ is substituted C₁-C₆ alkyl or C₃-C₈ cycloalkyl, the substituent is

and neither R^(13a) or R^(13b) is H, the preparation method for thecompound represented by formula I comprises that in organic solvent(e.g. selected from the group consisting of 1,4-dioxane, dichloromethaneand DMF), in the presence of condensing agent (e.g. HOBt and EDCI),reacting compound 6A with

to give compound 6B, then removing the protecting group of the aminogroup and conducting reductive amination to give compound I; theconditions of the amide reaction, the deprotection reaction and thereductive amination can be conventional conditions in the art;

is R⁵;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R^(6a), R^(6b), R^(6c), R^(6d),R^(13a) and R^(13b) are defined as above;

PG in the compound represented by formula 6B can be various conventionalamino protecting groups in the art, preferably Boc, for the purpose ofmaking certain reactive groups (e.g. amino group) not participate in thereaction when

reacts with compound 6A;

method 7:

when R⁵ is

R¹¹ is substituted C₁-C₆ alkyl or C₃-C₈ cycloalkyl, and the substituentis

R^(13b) and R^(13b) are the same, the preparation method for thecompound represented by formula I comprises that in organic solvent(e.g. selected from the group consisting of 1,4-dioxane, dichloromethaneand DMF), in the presence of condensing agent (e.g. HOBt and EDCI),reacting compound 7A with

to give compound 7B, then removing the protecting group of the aminogroup and conducting reductive amination to give compound I; theconditions of the amide reaction, the deprotection reaction and thereductive amination can be conventional conditions in the art;

is R⁵;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R^(6a), R^(6b), R^(6c), R^(6d) andR^(13a) are defined as above;

PG in the compound represented by formula 7B can be various conventionalamino protecting groups in the art, preferably Boc, for the purpose ofmaking certain reactive groups (e.g. amino group) not participate in thereaction when

reacts with compound I;

method 8:

when R⁵ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl

and substituted or unsubstituted C₃-C₈ heterocycloalkyl, the preparationmethod for the compound represented by formula I comprises that inorganic solvent (e.g. DMF and/or 1,4-dioxane), in the presence of base(e.g. N,N-diisopropylethylamine), conducting substitution reaction withcompound 8A and R⁵—X to give compound I; the conditions of thesubstitution reaction can be conventional conditions in the art; X ishalogen (e.g. bromine) or CH₃SO₃—;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

method 9:

when R⁵ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl

or substituted or unsubstituted C₃-C₈ heterocycloalkyl, the preparationmethod for the compound represented by formula I comprises that inorganic solvent (e.g. selected from the group consisting of1,2-dichloroethane, methanol and dioxane), in the presence of reductiveagent (e.g. sodium triacetoxyborohydride and/or sodiumcyanoborohydride), conducting reductive amination reaction with compound9A and R^(5a)—CHO to give compound I; the condition of the reductiveamination reaction can be conventional conditions in the art; R^(5a)CH₂— is R⁵;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

method 10:

when R⁵ is substituted C₁-C₆ alkyl, substituted C₃-C₈ cycloalkyl, or,substituted C₃-C₈ heterocycloalkyl, the substituent is

and R¹⁶ is hydroxyl, the preparation method for the compound representedby formula I comprises that in organic solvent (e.g. selected from thegroup consisting of DMF, dichloromethane and 1,4-dioxane), in thepresence of base (e.g. N,N-diisopropylethylamine), conductingsubstitution reaction with compound 10A and R^(5b)—OC(═O)—(CH₂)_(n2)—Xto give compound I; the condition of the substitution reaction and thehydrolysis reaction can be conventional conditions in the art; X ishalogen (e.g. bromine) or CH₃SO₃—; R^(5b) is C₁-C₆ alkyl(e.g. methyl);—(CH₂)_(n2) is the substituted C₁-C₆ alkyl (can be branched alkyl orstraight alkyl) in R⁵, substituted C₃-C₈ cycloalkyl, or, substitutedC₃-C₈ heterocycloalkyl;

is R⁵;

X, Y, Z, m, n, p, q, R¹, R², R³, R⁴, n₂, R^(6a), R^(6b), R^(6c) andR^(6d) are defined as above;

method 11:

when R⁵ is substituted C₁-C₆ alkyl, substituted C₃-C₈ cycloalkyl, thesubstituent is

(wherein at least one of R^(13a) and R^(13b) is hydrogen) or hydroxyl,or, unsubstituted C₃-C₈ heterocycloalkyl, the preparation method for thecompound represented by formula I comprises that in organic solvent(e.g. selected from the group consisting of 1,2-dichloroethane, methanoland/or dioxane), in the presence of reductive agent (e.g. sodiumtriacetoxyborohydride and/or sodium cyanoborohydride), conductingreductive amination reaction with compound 11A and PG-R^(5c)—CHO, thenremoving the protecting group to give compound I; the conditions of thereductive amination reaction and the deprotection reaction can beconventional conditions in the art; R^(5c)CH₂— is R⁵;

X, Y, Z, m, n, p, q, R¹, R², R³, R⁴, n₂, R^(6a), R^(6b), R^(6c) andR^(6d) are defined as above;

PG in the compound represented by formula 11B can be variousconventional amino protecting groups in the art, preferably Boc, for thepurpose of making certain reactive groups (e g amino group) notparticipate in the reaction when PG-R^(5c)—CHO reacts with compound 11A;

method 12;

when R⁵ is

R¹¹ is

and R^(12a) and R^(12b) are independently substituted or unsubstitutedC₁-C₂₀ alkyl, the preparation method for the compound represented byformula I comprises that in organic solvent, in the presence oftriphosgene, conducting condensation reaction with compound 11A andsubstituted or unsubstituted amino to give compound I;R^(12a)NR^(12b)—C(═O)— is R⁵;

X, Y, Z, m, n, p, q, R¹, R², R³, R⁴, n₂, R^(6a), R^(6b), R^(6c) andR^(6d) are defined as above;

method 13:

when R⁵ is substituted C₁-C₂₀ alkyl, or, substituted C₁-C₉heterocycloalkyl, the substituent is

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, substituted C₁-C₉heterocycloalkyl, or, C₃-C₁₂ cycloalkyl, and R^(13a) and R^(13b) areindependently hydrogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,C₃-C₁₂ cycloalkyl, borono, phospho, guanidino, thioureido,

the preparation method for the compound represented by formula Icomprises that in organic solvent, in the presence of reductive agent,conducting reductive amination reaction with compound 13A andPG-NR^(13a)—(CH₂)n-CHO, then removing the protecting group, followed bysubstitution reaction to give compound I; R^(13a)NR^(13b)—(CH₂)n- is R⁵;LG in the formula of the compound is a leaving group:

X, Y, m, n, p, q, R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

method 14:

when R⁵ is substituted C₁-C₂₀ alkyl, or, substituted C₁-C₉heterocycloalkyl, the substituent is

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, substituted C₁-C₉heterocycloalkyl, or, C₃-C₁₂ cycloalkyl, and R^(14a), R^(14b) andR^(14c) are independently hydrogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₃-C₁₂ cycloalkyl, borono, phospho, guanidino, thioureido

the preparation method for the compound represented by formula Icomprises that in organic solvent, in the presence of reductive agent,conducting reductive amination reaction with compound 14A andPG-NR^(14a)—(CH₂)n-CHO, then removing the protecting group, followed bysubstitution reaction to give compound I; R^(14b)NR^(14c)—(CH₂)n-R^(14a)is R⁵; LG in the formula of compound is a leaving group;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

method 15:

when R⁵ is substituted C₁-C₂₀ alkyl, or, substituted C₁-C₉heterocycloalkyl, the substituent is

C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, substituted C₁-C₉heterocycloalkyl, or, C₃-C₁₂ cycloalkyl, and R^(13a) and R^(13b) areindependently hydrogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,C₃-C₁₂ cycloalkyl, borono, phospho, guanidino, thioureido,

the preparation method for the compound represented by formula Icomprises that in organic solvent, in the presence of reductive agent,conducting substitution reaction with compound 15A and LG-(CH₂)n-CN,followed by addition reaction to give compound I; LG in the formulacompound is a leaving group;

X, Y, m, n, p, q, R¹, R², R³, R⁴, R⁵, R^(6a), R^(6b), R^(6c) and R^(6d)are defined as above;

after the completing of the preparation method for thenitrogen-containing fused heterocyclic compound, the post-treatment ispreferably conducted; the methods and conditions of the post-treatmentcan be conventional methods and conditions for the post-reactiontreatment in the art, preferably comprising washing the reaction system,drying, filtering, evaporating to dryness, then being subjected tocolumn chromatography; or, the reaction system is distilled to removethe solvent, washed, and filtered; or the reaction system is distilledto remove the solvent, subjected to thin layer chromatography.

The present invention also provides a compound II, which is selectedfrom the group consisting of

wherein m, n, p, q, X, Y, R¹, R², R³, R⁴, R⁵, R^(5a), R^(5b), R^(5c),R^(6a), R^(6b), R^(6c), R^(6d), R⁸, R^(13a) and PG are defined as above.

Preferably, the compound II is selected from the group consisting of

The present invention also provides a use of the nitrogen-containingfused heterocyclic compound, the pharmaceutically acceptable salt, theenantiomer, the diastereomer, the tautomer, the solvate, the metaboliteor the drug precursor thereof in manufacturing medicament, themedicament is used for the prevention or the treatment of disorderassociated with abnormal cell cycle regulation; the “disorder associatedwith abnormal cell cycle regulation” is preferably “disorder associatedwith abnormality of cyclin-dependent kinase (preferably CDK4 and/orCDK6)”, more preferably tumor, most preferably malignant tumor (e.g.breast cancer).

The present invention also provides a use of the nitrogen-containingfused heterocyclic compound, the pharmaceutically acceptable salt, theenantiomer, the diastereomer, the tautomer, the solvate, the metaboliteor the drug precursor thereof in manufacturing an inhibitor ofcyclin-dependent kinase (preferably CDK4 and/or CDK6).

The present invention also provides a use of the nitrogen-containingfused heterocyclic compound, the pharmaceutically acceptable salt, theenantiomer, the diastereomer, the tautomer, the solvate, the metaboliteor the drug precursor thereof in manufacturing medicament having tumorcell inhibitory activity; the tumor cell is preferably cancer cell; thecancer cell is preferably breast cancer cell; the breast cancer cell ispreferably selected from the group consisting of breast cancer cellMCF-7, T-47D and ZR-75-1.

The present invention also provides a composition, which comprises thenitrogen-containing fused heterocyclic compound, the pharmaceuticallyacceptable salt, the enantiomer, the diastereomer, the tautomer, thesolvate, the metabolite or the drug precursor thereof, and at least apharmaceutical excipient.

The dose of the nitrogen-containing fused heterocyclic compound, thepharmaceutically acceptable salt, the enantiomer, the diastereomer, thetautomer, the solvate, the metabolite or the drug precursor thereof canbe a therapeutically effective dose.

The select of the pharmaceutical excipient varies depending on the routeof administration and the characteristic of action, can generally befillers, diluents, adhesives, wetting agents, disintegrants, lubricants,emulsifiers, suspending agents etc. that are conventional in the art.

The route of administration of the pharmaceutical composition can beoral administration, injection (intravenous, intramuscular, subcutaneousand intracoronary), sublingual administration, buccal administration,rectal administration, transurethral administration, transvaginaladministration, nasal administration, inhaled administration or topicaladministration, preferably oral administration.

In the present invention, unless otherwise specified, the followingterms in the description and the claims of the invention have thefollowing meanings:

The term “halogen” is preferably fluorine, chlorine, bromine, iodine,more preferably fluorine.

The term “C₁-C₂₀ alkyl” refers to a straight chain or branched saturatedhydrocarbon group containing 1 to 20 carbon atoms. Alkyl can beoptionally substituted with one or more than one substituent describedin the present invention. Examples of alkyl include but not limited tomethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), n-propyl (n-Pr, —CH₂CH₂CH₃),isopropyl (i-Pr, —CH(CH₃)₂), n-butyl(n-Bu, —CH₂CH₂CH₂CH₃),2-methylpropyl or isobutyl (i-Bu, —CH₂CH(CH₃)₂), 1-methylpropyl orsec-butyl (s-Bu, —CH(CH₃)CH₂CH₃), tert-butyl (t-Bu, —C(CH₃)₃), n-pentyl(—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), n-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),4-methylpentyl(—CH₂CH₂CH₂CH(CH₃)CH₃), 3-methylpentyl(—CH₂CH₂CH(CH₃)CH₂CH₃), 2-methylpentyl (—CH₂CH(CH₃)CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃),3,3-dimethylbutyl (—CH₂CH₂CH₂(CH₃)₂CH₃), 2,2-dimethylbutyl(—CH₂C(CH₃)₂CH₂CH₃), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂),2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl(—CH(CH₃)C(CH₃)₃), n-heptyl, n-octyl etc.

In the present invention, the term “alkenyl” refers to a straight,branched, or cyclic non-aromatic hydrocarbon group containing thespecified number of carbon atoms and at least one carbon-carbon doublebond. Alkenyl is preferably containing one carbon-carbon double bond,and up to four non-aromatic carbon-carbon double bonds can be present.Thus, “C₂₋₁₂ alkenyl” refers to an alkenyl group having 2 to12 carbonatoms. “C₂₋₆ alkenyl” refers to an alkenyl group having 2 to 6 carbonatoms, including vinyl, propenyl, butenyl, 2-methylbutenyl andcyclohexenyl. The straight chain, branched chain or cyclic portion ofalkenyl can contain double bond, and if it is substituted alkenyl, thealkenyl can be substituted.

The term “alkynyl” refers to a straight, branched, or cyclic hydrocarbongroup containing the specified number of carbon atoms and at least onecarbon-carbon triple bond. Up to three carbon-carbon triple bonds can bepresent. Thus, “C₂₋₁₂ alkynyl” refers to an alkynyl group having 2 to12carbon atoms. “C₂₋₆ alkynyl” refers to an alkynyl group having 2 to 6carbon atoms, including but not limited to ethynyl, propynyl, butynyl,and 3-methylbutynyl.

The term “C₁-C₂₀ alkoxy” refers to C₁-C₂₀ alkyl connected by the oxygenatom; the C₁-C₂₀ alkyl is defined as above.

The term “C₁-C₂₀ alkylthio” refers to C₁-C₂₀ alkyl connected by thesulfur atom; the C₁-C₂₀ alkyl is defined as above.

The term “C₁-C₂₀ silyl” refers to C₁-C₂₀ alkyl connected by the siliconatom; the C₁-C₂₀ alkyl is defined as above.

The term “C₃-C₁₂ cycloalkyl” refers to a cyclic hydrocarbon group thatcontains 3 to 12 ring-forming carbon atoms, can be saturated orpartially unsaturated (contain 1 or 2 double bonds, but none of therings have a fully conjugated 7C electron system), and does not containheteroatom; including a monocycle containing 3 to 12 carbon atoms or abicycle or tricycle containing 7 to 12 carbon atoms (including spiroring, bridged ring and fused ring); wherein one or more than onehydrogen atoms in the ring can be independently optionally substitutedwith one or more than one substituent described herein, and the carbonatoms can be oxidized. A bicyclic carbon ring containing 7 to12 atomscan be bicyclic [4,5], [5,5], [5,6] or [6,6] system, and a bicycliccarbon ring containing 9 or 10 atoms can be bicyclic[5,6] or [6,6]system. Suitable cycloalkyl group include, but is not limited to,cycloalkyl, cycloalkenyl and cycloalkynyl, e.g. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl,1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl,1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-enyl, cyclohexadienyl,cycloheptyl, cyclooctyl, cyclononyl, cyclononyl, cycloundecyl,cyclododecyl, adamantyl etc. Depending on the structure, cycloalkyl canbe a monovalent or divalent group, i.e.cycloalkylene.

The term “heterocycloalkyl” refers to a 3 to 10 membered monocyclic orpolycyclic group (including spiro ring, bridged ring and fused ring)containing 1 to 6 heteroatoms (selected from the group consisting of N,S, B, P, Si, O and Se), wherein each ring can contain one or more thanone double bonds, but none of the rings has a fully conjugated 7Celectron system; heteroatom can be substituted or unsubstituted, and Natom can be quaternized. Heterocyclic system can be attached to the mainstructure via any heteroatom or carbon atom to form a stable compound.One or more than one hydrogen atoms on the ring are independentlyoptionally substituted with one or more than one substituent describedherein. For example, 3 to7 membered monocycle (1 to 6 carbon atoms and 1to 3 heteroatoms selected from the group consisting of N, O, P, B, Si, Sand Se, wherein N, S, B, P or Se is optionally substituted with one ormore than one oxygen atoms to form groups like NO, NO₂, BOH, SO, SO₂,PO, PO₂ and SeO, meanwhile —CH₂— group can be optionally replaced with—C(═O)—, —C(═S)— or —C(═N)—; —SH₂— group can be optionally replaced with—S(═O)—, —S(═O)₂—, —S(═N)— or —S(═N)₂—; when the ring is a 3 memberedring, there is only one heteroatom), or a bicyclic ring formed by 7 to10 atoms (4 to 9 carbons atoms and 1 to 3 heteroatoms selected from thegroup consisting of N, O, P, B, Si and S, wherein N, S, B or P isoptionally substituted with one or more than one oxygen atom to formgroups like NO, NO₂, BOH, SO, SO₂, PO, PO₂, SeO, meanwhile —CH₂— groupcan be optionally replaced with —C(═O)—. Depending on the structure, theheterocyclic group can be a monovalent or a divalent group, i.e.heterocyclylene. In some embodiments, N atom in the nitrogen-containingheterocycle can be oxidized to form nitrogen oxide.

The term “heteroaryl” refers to a 3 to 10 membered monocyclic orpolycyclic aromatic system containing 1 to 6 heteroatoms (selected fromthe group consisting of N, S, B, P, Si, O and Se, wherein bicyclicheteroaromatic ring, tricyclic heteroaromatic ring or tetracyclicheteroaromatic ring system forms the ring in a fused form, and whereinN, S, B, P or Se is optionally substituted with one or more than oneoxygen atom to form groups like NO, NO₂, BOH, SO, SO₂, PO, PO₂ and SeO,N atom can be quaternized, one or more than one hydrogen atom on thering is independently optionally substituted with one or more than onesubstituent described herein. Heteroaryl can be attached to the mainstructure via any heteroatom or carbon atom to form a stable compound.Heteroaryl includes, but is not limited to, monocycleformed by 3 to 7atoms, or bicyclic ring formed by 7 to 10 atoms, or tricyclic ringformed by 10 to 15 atoms. A bicyclic ring containing 7 to 10 atoms canbe bicyclic[4,5], [5,5], [5,6] or [6,6] system, tricyclic ringcontaining 10 to 15 atoms can be tricyclic[5,5,6], [5,7,6] or [6,5,6]system. Depending on the structure, the heteroaryl can be a monovalentor divalent group, i.e. heteroarylene. Examples of heteroaryl includebut not limited to 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g. 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl),triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl,1,3,4-thiadiazole-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl,benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, benzimidazolyl,benzoxazolyl, quinoxalinyl, 1,8-naphthyridinyl, benzofuranyl,benzothienyl, benzothiazolyl, indolyl (e.g. 2-indolyl), purinyl,quinolyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g,1-isoquinolyl, 3-isoquinolinyl or 4-isoquinolinyl), tetrahydronaphthyl,benzopyrazolyl, acridinyl, benzimidazolyl, benzoindolyl,benzoisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzo[d]imidazo[2,1-b]thiazolyl, benzofuranyl, benzonaphthofuranyl, benzothiadiazolyl,benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl,benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl,o-naphthyridinyl, dibenzofuranyl, imidazopyridyl, imidazothiazolyl,indazolyl, indolizinyl, indolyl, isobenzothienyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl,decahydroindolyl, decahydroisoindolyl, oxazolidinedionyl, oxazolidinyl,oxazolopyridinyl, oxazolyl, oxiranyl, tea-diazobenzene ,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridyl,quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo[3,4-c]pyridinyl , pyrazolo[2′,1′:2,3]oxazolo[4,5-c]pyridyl,imidazo[2′,1′:2,3]thiazolo[4,5-c]pyridyl,imidazo[2′,1′:2,3]thiazolo[4,5-b]pyridyl,imidazo[2′,1′:2,3]thiazolo[5,4-b]pyridyl, pyrazolo[2′, 1′:2,3]thiazolo[4,5-b]pyrazinyl, 1H-benzo[4,5]thieno[2,3-d]imidazolyl,1-methyl-1H-benzo[4,5]thieno[2,3-d]imidazolyl,imidazo[2′,1′:2,3]thiazolo[4,5-b]pyrazinyl,imidazo[2′:2,3]thiazolo[5,4-b]pyridyl ,imidazo[2′:2,3]thiazolo[4,5-c]pyridyl,1H-benzo[f]imidazo[4,5-b][1,4]thiazepine etc.

The term “aryl” refers to monocyclic, bicyclic, and tricyclic carbonring system, wherein at least one ring system is aromatic, each ringsystem contains 3 to 7 atoms, one or more than one hydrogen atom on thering is independently optionally substituted with one or more than onesubstituent described herein. The term “aryl” can be usedinterchangeably with the term “aromatic ring”, e.g. but not limited to,phenyl, naphthyl and anthracene. Depending on the structure, aryl can bea monovalent group or a divalent group, i.e. arylene.

The term “pharmaceutically acceptable salt” refers to a salt formed by asuitable non-toxic organic acid, inorganic acid, organic base orinorganic base with compound I, which retains the biological activity ofcompound I. The organic acid can be various conventional organic acidsin the art and capable of salt formation, preferably selected from thegroup consisting of methanesulfonic acid, p-toluenesulfonic acid, maleicacid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid,formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalicacid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonicacid and salicylic acid. The inorganic acid can be various conventionalinorganic acid in the art and capable of salt formation, preferablyselected from the group consisting of hydrochloric acid, sulfuric acidand phosphoric acid. The organic base can be various conventionalorganic base in the art and capable of salt formation, preferablyselected from the group consisting of pyridines, imidazoles, pyrazines,indoles, purines, tertiary amines and anilines The tertiary aminesorganic base is preferably triethylamine and/orN,N-diisopropylethylamine The anilines organic base is preferablyN,N-dimethylaniline. The pyridines organic base is preferably selectedfrom the group consisting of pyridine, methylpyridine,4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic basecan be various conventional inorganic base in the art and capable ofsalt formation, preferably selected from the group consisting of alkalimetal hydride, alkali metal hydroxide, alkali metal alkoxide, potassiumcarbonate, sodium carbonate, lithium carbonate, cesium carbonate,potassium bicarbonate and sodium bicarbonate. The alkali metal hydrideis preferably sodium hydride and/or potassium hydride. The alkali metalhydroxide is preferably selected from the group consisting of sodiumhydroxide, potassium hydroxide and lithium hydroxide. The alkali metalalkoxide is preferably selected from the group consisting of sodiummethoxide, sodium ethoxide, potassium tert-butoxide and sodiumtert-butoxide.

In the present invention, the “solvate” refers to a substance formed bythe compound I and a suitable solvent. The solvent is preferably wateror an organic solvent.

Without violating the common sense in the art, the above preferredconditions can be arbitrarily combined, then preferred embodiments ofthe present invention are obtained.

The reagents and raw materials used in the present invention arecommercially available.

The positive and progressive effect of the present invention is that thecompound of the present invention exhibits high selectivity and highinhibitory activity with respect to CDK4 and CDK6 at a molecular level,an excellent inhibitory activity with respect to breast cancer cells ata cellular level, and significant inhibition of tumor cell proliferationassociated with cyclin-dependent kinase activity at an animal level. Thecompound also exhibits good stability with respect to liver microsome ofhuman or mouse etc. without significant inhibition of metabolic enzymes,good in vivo absorption in mice and rats, high bioavailability and gooddruggability.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The structure of all the compound of the present invention can beidentified by nuclear magnetic resonance (¹H NMR) and/or massspectrometry (MS). ¹H NMR chemical shift (δ) is recorded in PPM (10⁻⁶).NMR was determined on a Bruker AVANCE-400 spectrometer.

LC-MS was determined on Agilent 1200 HPLC/6120 mass spectrometer.

The thin-layer silica gel was Yantai Huanghai HSGF254 or Qingdao GF254silica gel plate. Column chromatography generally uses Yantai Huanghai200-300 mesh silica gel as carrier.

Preparation Embodiment 1

Step 1:

6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole(200 mg, 0.73765mmol) (compound represented by formula 1-a), bis(pinacolato)diboron (280mg, 1.1 mmol), tricyclohexylphosphine (37 mg, 0.1320 mmol), potassiumacetate (218 mg, 2.221 mmol) and palladium acetate (19 mg, 0.1148 mmol)were added to dimethyl sulfoxide (2 mL), and the mixture was stirredunder nitrogen atmosphere at 90° C. for 2 hours. After cooling to roomtemperature, the reaction solution was diluted with 10 mL ethyl acetateand filtered. The filtrate was washed with saturated brine, dried overanhydrous sodium sulfate. The organic layer was concentrated andpurified by silica gel column chromatography (ethyl acetate/n-hexane 0to 50%) to give compound4-fluoro-1sopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazolerepresented by formula 1-b (180 mg, 0.5657 mmol). LC-MS: m/z:(M+H)⁺=319.2.

Step 2:

2,4-Dichloro-5-fluoropyrimidine (110 mg, 0.65880 mmol) (represented byformula 1-b),4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazole(180 mg, 0.5657 mmol), (bis(triphenylphosphine))palladium dichloride (30mg) were added to 2M sodium carbonate solution (1 mL) and ethyleneglycol dimethyl ether (3 mL), and the mixture was stirred under nitrogenatmosphere at 85° C. for 2 hours. After cooling to room temperature, thereaction solution was diluted with 10 mL ethyl acetate, washed withsaturated brine, and dried over anhydrous sodium sulfate. The organicphase was concentrated and recrystallized from acetonitrile, filtered togive compound6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazolerepresented by formula 1-c (135 mg, 0.4183 mmol). LC-MS: m/z:(M+H)⁺=323.2.

Step 3:

6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazole(110 mg, 0.3409 mmol) (represented by formula 1-c), tert-butyl2-amino-7,8-dihydro-1,6-naphthyridine-6-carboxylate (85 mg, 0.3410mmol), cesium carbonate (222 mg, 1.1507 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.02938 mmol),tris(dibenzylideneacetone)dipalladium (13 mg) were added to 1,4-dioxane(3 mL), and the mixture was stirred under nitrogen atmosphere at 110° C.for 12 hours. After cooling to room temperature, the reaction solutionwas diluted with 10 mL ethyl acetate, filtered, and the filtrate wasconcentrated and purified by silica gel column chromatography(dichloromethane/methanol 0-10%) to give tert-butyl2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylaterepresented by formula 1-d (110 mg, 0.2054 mmol). LC-MS: m/z:(M+H)⁺=536.2.

Preparation Embodiment 2

Step 1

Methyl 2-methyl nicotinate (1.9 g, 13.0 mmol) (represented by formula2-a) and trichloroisocyanuric acid (3.7 g, 16.0 mmol) (represented byformula 2-b) were dissolved in dichloromethane (50 mL), and the mixturewas stirred at room temperature for 18 hours. Then saturated aqueoussodium bicarbonate solution was added to the reaction solution, themixture was extracted with dichloromethane (30 mL×2), thedichloromethane layers were combined, dried over anhydrous sodiumsulfate, filtered, and the filtrate was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate=100% to 75%)to give methyl 2-(chloromethyl)nicotinate represented by formula 2-c(1.9 g, 10.3 mmol) as a pale yellow solid. LC-MS: m/z: (M+H)⁺=186.

Step 2:

Methyl 2-(chloromethyl)nicotinate (1.9 g, 10 mmol) (represented byformula 2-c) and m-chloroperoxybenzoic acid (2 g, 11.6 mmol) weredissolved in dichloromethane (50 mL), and the mixture was stirred atroom temperature for 16 hours. Then saturated aqueous sodium bicarbonatesolution was added to the reaction solution, the mixture was extractedwith dichloromethane (60 mL×2), the dichloromethane layers werecombined, dried over anhydrous sodium sulfate, filtered, and thefiltrate was purified by column chromatography (silica gel, petroleumether/ethyl acetate=100% to 0%) to give methyl2-(chloromethyl)nicotinate 1-oxide represented by formula 2-d (15 g, 7.4mmol)as a pale yellow solid. LC-MS: m/z: (M+H)⁺=202.2.

Step 3:

Methyl 2-(chloromethyl)nicotinate 1-oxide (represented by formula 2-d)(1.9 g, 9.4 mmol) was dissolved in phosphorous oxychloride (9 mL), themixture was stirred under reflux for 5 hours, then cooled and pouredinto ice water. Then saturated aqueous sodium bicarbonate solution wasadded, the mixture was extracted with dichloromethane (60 mL×2), andmethylene chloride layers were combined, dried over anhydrous sodiumsulfate, filtered, and the filtrate was purified by columnchromatography (silica gel, petroleum ether/ethyl acetate=100%-0%) togive methyl 6-chloro-2-(chloromethyl)nicotinate represented by formula2-e (0.88 g, 4.0 mmol) as a pale yellow solid. LC-MS m/z: (M+H)⁺=240.2.

Step 4:

Methyl 6-chloro-2-(chloromethyl) nicotinate (represented by formula 2-e)(70 mg, 0.32 mmol) and N′,N′-dimethylethylenediamine (represented byformula 2-f) (50 mg, 0.57 mmol) were dissolved in tetrahydrofuran (10mL), and the mixture was stirred at room temperature for 16 hours. Thereaction solution was concentrated and purified by thin-layerchromatography (silica gel, dichloromethane/methanol=10/1) to give2-chloro-6-(2-(dimethylamino)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-onerepresented by formula 2-g (40 mg, 0.17 mmol) as a pale yellow solid.LC-MS: m/z: (M+H)⁺=240.2.

Preparation Embodiment 3

Step 1:

6-Bromo-4-fluoro-1-cyclopentyl-2-methyl-benzimidazole (200 mg, 0.6729mmol) (represented by formula 3-a), bis(pinacolato)diboron (260 mg, 1.1mmol), tricyclohexylphosphine (37 mg, 0.1320 mmol), potassium acetate(218 mg, 2.221 mmol) and palladium acetate (19 mg, 0.1148 mmol) wereadded to dimethyl sulfoxide (2 mL), and the mixture was stirred undernitrogen atmosphere at 90° C. for 2 hours. After cooling to roomtemperature, the reaction solution was diluted with 10 mL ethyl acetateand filtered. The filtrate was washed with saturated brine, dried overanhydrous sodium sulfate. The organic layer was concentrated andpurified by silica gel column chromatography (ethyl acetate/n-hexane0-50%) to give4-fluoro-1-cyclopentyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazolerepresented by formula 3-b (180 mg, 0.523 mmol). LC-MS: m/z:(M+H)⁺=345.2.

Step 2:

2,4-Dichloro-5-fluoropyrimidine (110 mg, 0.65880 mmol),4-fluoro-1-cyclopentyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazole(180 mg, 0.523 mmol) (represented by formula 3-b),(bis(triphenylphosphine)palladium dichloride (30 mg) were added to 2Msodium carbonate solution (1 mL) and ethylene glycol dimethyl ether (3mL), and the mixture was stirred under nitrogen atmosphere at 85° C. for2 hours. After cooling to room temperature, the reaction solution wasdiluted with 10 mL ethyl acetate, washed with saturated brine, and driedover anhydrous sodium sulfate. The organic phase was concentrated andrecrystallized from acetonitrile to give6-(2-chloro-5-fluoro-pyrimidine-4-yl)-4-fluoro-1-cyclopentyl-2-methyl-benzimidazolerepresented by formula 3-c (135 mg, 0.37 mmol). LC-MS: m/z: (M+H)⁺=349.8

Step 3:

5-(2-Chloro-5-fluoropyrimidin-4-yl)-1-cyclopentyl-7-fluoro-2-methyl-1H-benzo[d]imidazole)(360 mg, 1.03 mmol) (represented by formula 3-c) was dissolved in 5 mLdioxane, tert-butyl2-amino-7,8-dihydro-1,6-naphthyridine-6(5H)-methylcarboxylate (257 mg,1.03 mmol), tris(dibenzylideneacetone)dipalladium (94 mg, 0.10 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (119 mg, 0.21 mmol) andcesium carbonate (504 mg, 1.55 mmol) were added, and the mixture wasstirred under argon atmosphere at 110° C. for 18 hours. The reactionsolution was filtered and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the compoundrepresented by formula 3-d as a yellow solid 340 mg, yield 82%. LC-MS:m/z: (M+H)⁺=548.2.

Preparation Embodiment 4

Step 1:

Cyclopropylamine (30 g, 525.5 mmol) and diisopropylacetamide (80 g,790.6 mmol) were dissolved in dichloromethane (200 mL), the mixture wascooled to 0° C. and acetic anhydride was slowly added dropwise (115 g,1126 mmol). After the completion of the addition, the mixture wasstirred at room temperature for 16 hours, evaporated under reducedpressure, then ethyl acetate and potassium carbonate (144 g, 1050 mmol)were added. The mixture was stirred at room temperature for 16 hours,filtered, and evaporated under reduced pressure to give 55 gN-cyclopropylacetamide represented by formula 4-c.

Step 2:

N-cyclopropylacetamide (54 g, 544.7 mmol), 4-bromo-2,6-difluoroaniline(54.6 g, 263 mmol) and N,N-diisopropylethylamine (50.8 g, 393 mmol) weredissolved in toluene (250 mL), then phosphorus oxychloride (40.3 g, 263mmol) was slowly added. The mixture was stirred at 100° C. for 16 hours,evaporated under reduced pressure, cooled to room temperature, thendichloromethane was added, washed with saturated sodium bicarbonatesolution, and the organic layer was dried over anhydrous sodium sulfate,concentrated, slurried with ethyl acetate, filtered, and the solid wasdried to give 43.6 gN′-(4-bromo-2,6-difluoro-phenyl)-N-cyclopropyl-acetamidine representedby formula 4-d. LC-MS m/z: (M+H)⁺=289.1, 291.1.

Step 3:

N′-(4-bromo-2,6-difluoro-phenyl)-N-cyclopropyl-acetamidine(43.6 g, 151mmol) was dissolved in N,N-dimethylformamide (300 mL), potassiumtert-butoxide (28 g, 249.5 mmol) was added slowly, and the mixture wasstirred at 100° C. for 3 hours, cooled to room temperature. Then 1.5 Lwater was added, the mixture was filtered, the solid was washed withwater and distilled under reduced pressure to remove water, thenslurried with a mixed solvent of dichloromethane/petroleum ether=1/2,and filtered to give 35 g6-bromo-1-cyclopropyl-4-fluoro-2-methyl-benzimidazole represented byformula 4-f. LC-MS m/z: (M+H)⁺=269.1, 271.1.

Step 4:

6-Bromo-1-cyclopropyl-4-fluoro-2-methyl-benzimidazole (15 g, 55.7 mmol),bis(pinacolato)diboron (16 g, 63 mmol), potassium acetate (10 g, 102mmol), tricyclohexylphosphine (1.5 g, 5.3 mmol) and palladium acetate (1g, 4.45 mmol) were dissolved in DMSO (60 mL), and the mixture wasstirred under argon atmosphere at 80° C. for 16 hours. The reactionsolution was cooled to room temperature, filtered, diluted with waterand extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and concentrated to give a crude product, whichwas slurried with ethyl acetate. Partial product was collected byfiltration, and the filtrate was concentrated and purified by columnchromatography (petroleum ether/ethyl diacid=100% to 25%) to obtainpartial product, the product was combined to give 5 g1-cyclopropyl-4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazolerepresented by formula 4-e. LC-MS m/z: (M+H)⁺=317.2.

Step 5:

1-Cyclopropyl-4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzimidazole(5 g, 15.8 mmol), 2,4-dichloro-5-fluoro-pyrimidine (3 g, 18.0 mmol),sodium carbonate (3 g, 28.3 mmol) anddichlorobis(triphenylphosphine)palladium (550 mg, 0.83 mmol) weredissolved in a mixed solution of ethylene glycol dimethyl ether (70 mL)and water (10 mL), the mixture was stirred under argon atmosphere at 80°C. for 16 hours. The reaction solution was cooled to room temperature,filtered, and the ethylene glycol dimethyl ether was distilled off underreduced pressure. The residue was diluted with water and extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and concentrated to give a crude product, which was slurriedwith acetonitrile, filtered and dried to give 4.5 g6-(2-chloro-5-fluoro-pyrimidin-4-yl)-1-cyclopropyl-4-fluoro-2-methyl-benzimidazolerepresented by 4-g. LC-MS m/z: (M+H)⁺=321.2.

Step 6:

6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-1-cyclopropyl-4-fluoro-2-methyl-benzimidazole(4.5 g, 14 mmol), tert-butyl2-amino-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (3.8 g, 15 mmol),cesium carbonate (9 g, 27.6 mmol), tris(dibenzylideneacetone)dipalladium(900 mg, 0.98 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(500 mg, 0.86 mmol) were dissolved in dioxane (100 mL), the mixture wasstirred under argon atmosphere at 90° C. for 16 hours, then distilledunder reduced pressure to remove the solvent, diluted with a mixedsolvent of dichloromethane and methanol, filtered. The filtrate wasdried over anhydrous sodium sulfate, concentrated, and purified bycolumn chromatography (dichloromethane/methanol=100% to 90%) to give 7 gtert-butyl2-((5-fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylaterepresented by 4-h. LC-MS m/z: (M+H)⁺=534.2.

Preparation Embodiment 5

The mixture of tert-butyl2-amino-7-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate andtert-butyl2-amino-5-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate(represented by formula 5-a and 5-b, supplied by KERMANDA) (3.0 g, 11.4mmol) was isolated via chiral liquid phase preparation to give fourisomers, which were tert-butyl2-amino-5-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Peak 1,0.5658 g), tert-butyl2-amino-5-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Peak 3,0.6884 g), tert-butyl2-amino-7-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Peak 2,0.4281 g), tert-butyl2-amino-7-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (Peak 4,0.6460 g). LC-MS m/z: (M+H)⁺=264.2.

Preparation Embodiment 6

Step 1:

DIPEA (1.757 g, 13.59 mmol) and 2-bromoethanol (1.446 g, 11.57 mmol)were added to a suspension ofN-(4-(3-tert-butyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(1.3 g, 2.892 mmol) (represented by formula I-68) in anhydrous DMF (22mL) under argon atmosphere at room temperature. The reaction mixture wasstirred at 85° C. for 12 hours. TLC monitored that most of the rawmaterials had already reacted. The reaction mixture was cooled to roomtemperature and diluted with 20 mL water. The precipitated solid wasfiltered and the filter cake was washed with water (10 mL×3) and driedin vacuo to give a yellow solid2-(2-((4-(3-tert-butyl-7-fluoro-2-methyl-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)ethanolrepresented by formula 3-b (1.1 g, 2.229 mmol) as a pale yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 8.40 (d, J=3.8 Hz, 1H), 8.39 (d, J=1.3Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J=11.2 Hz, 1H),7.36 (d, J=8.5 Hz, 1H), 3.78-3.72 (m, 2H), 3.70 (s, 2H), 2.95 (dd,J=10.7, 4.6 Hz, 4H), 2.88 (s, 3H), 2.80-2.75 (m, 2H), 1.91 (s, 9H).

LC-MS m/z:(M+H)⁺=494.2.

Step 2:

Thionyl chloride (7.954 g, 66.86 mmol) was added to a suspension of2-((4(4-(3-tert-butyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)ethanol(1.1 g, 2.229 mmol) (represented by formula 6-a) in dichloromethane (40mL) at room temperature under argon atmosphere. The mixture was stirredat room temperature for 16 hours. LCMS monitored the reaction wascomplete. The solvent was removed by distillation under reducedpressure. The solid residue was dissolved in 100 mL mixed solvent ofdichloromethane and methanol (10:1, v/v). The organic phase was washedto neutral with saturated aqueous sodium bicarbonate solution, thenwashed with saturated brine (50 mL×2). The separated organic phase wasevaporated to dryness on a rotary evaporator, the residue was purifiedby biotage preparative liquid chromatography(methanol/dichloromethane=1% to 5%, v/v, 10 g silica gel column) to giveyellow solidN-(4-(3-tert-butyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-6-(2-chloroethyl)-7,8-dihydro-5H-1,6-naphthyridin-2-amine(600 mg, 1.172 mmol) as a pale yellow solid.

¹H NMR (400 MHz, Chloroform-d) δ 8.41-8.36 (m, 2H), 8.22 (d, J=8.5 Hz,1H), 7.91 (s, 1H), 7.75 (d, J=11.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H),3.72-3.67 (m, 4H), 3.00-2.90 (m, 6H), 2.87 (s, 3H), 1.91 (s, 9H).

LC-MS m/z:(M+H)⁺=512.2.

Embodiment 3

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(70 mg, 0.1607 mmol) (represented by formula I-1), 2-bromopropane (40mg, 0.32523 mmol), N,N-diisopropyl ethylamine (50 mg) were added to 1 mLDMF, and the mixture was stirred at 90° C. for 12 hours. The reactionsolution was concentrated and purified by silica gel columnchromatography (dichloromethane/methanol 0 to 10%) to giveN-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-6-isopropyl-7,8-dihydro-5H-1,6-naphthyridin-2-aminerepresented by 1-3 (30 mg, 0.06281 mmol). ¹H-NMR (400 MHz, DMSO-d₆) δ9.90(s, 1H), 8.68(d, 1H, J=3.6 Hz), 8.32(d, 1H, J=1.2 Hz), 8.06(d, 1H,J=8.4 Hz), 7.69(d, 1H, J=12.4 Hz), 7.48(d, 1H, J=1.2 Hz), 4.82-4.89(m,1H), 3.63(s, 2H), 2.81(br, 4H), 1.97-2.04(m, 1H), 1.64(d, 6H, J=6.8 Hz),1.08(d, 6H, J=6.0 Hz).LC-MS: m/z: (M+H)⁺=478.2.

Embodiment 4

Step 1:

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), N-boc-sarcosine (46mg, 0.24312 mmol) (represented by formula I-3-a), HOBt (25 mg, 0.18502mmol), EDCI (36 mg, 0.18779 mmol) were added to 1 mL DMF, and themixture was stirred at room temperature for 12 hours. The reactionsolution was concentrated and purified by silica gel columnchromatography (dichloromethane/methanol 0 to 10%) to give tert-butylN-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2-oxoethyl)-N-methyl-carbamaterepresented by formula I-4-b (50 mg, 0.08241 mmol). LC-MS: m/z:(M+H)⁺=607.2.

Step 2:

Tert-butylN-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-oxoethyl)-N-methylcarbamate(50 mg, 0.08241 mmol) (represented by formula I-4-b) was added to 2MHCl/MeOH solution (2 mL), and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was concentrated to give1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidine-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-(methylamino)ethanonerepresented by formula I-4 (30 mg, 0.05922 mmol). ¹H-NMR (400 MHz,CD₃OD) δ 8.96-8.97(m, 1H), 8.62(s, 1H), 8.22-8.26(m, 2H), 7.56 (dd, 1H,J=8.8, 2.8 Hz), 5.16-5.23(m, 1H), 4.87(s, 1H), 4.78(s, 1H), 4.32(s, 1H),4.27(s, 1H), 4.08(t, 1H, J=6.0 Hz), 3.92(t, 1H, J=6.0 Hz), 3.37-3.38(m,2H), 3.24-3.27(m, 2H), 3.02(s, 3H), 2.82(d, 3H, J=2.8 Hz), 1.84(d, 6H,J=6.8 Hz).LC-MS: m/z: (M+H)⁺=507.2.

Embodiment 5

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), N,N-dimethylglycine(20.5 mg, 0.199 mmol), HOBt (25 mg, 0.18502 mmol), EDCI (36 mg, 0.18779mmol) were added to 1 mL DMF, and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give2-(dimethylamino)-1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)ethanonerepresented by formula I-5 (10 mg, 0.01921 mmol). ¹H-NMR (400 MHz,CD₃OD) δ 8.50(d, 1H, J=3.6 Hz), 8.26-8.30(m, 2H), 7.78(d, 1H, J=12 Hz),7.56(d, 1H, J=8.4 Hz), 4.86-4.90(m, 2H), 4.86(s, 2H), 4.71(s, 1H),3.92(t, 2H, J=5.6 Hz), 3.00(t, 1H, J=5.6 Hz), 2.92(t, 1H, J=5.6 Hz),2.69(s, 3H), 2.35(s, 3H), 2.34(s, 3H), 1.74(d, 6H, J=7.2 Hz).LC-MS:(M+H)⁺=521.2.

Embodiment 6

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), 2-methoxyacetic acid(18 mg, 0.1998 mmol), HOBt (25 mg, 0.18502 mmol), EDCI (36 mg, 0.18779mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-methoxyethanone(60 mg, 0.1182 mmol). ¹H-NMR (400 MHz, CD₃OD) δ 8.54(d, 1H, J=3.6 Hz),8.33(s, 1H), 8.23-8.27(m, 1H), 7.76(d, 1H, J=11.6 Hz), 7.57(d, 1H, J=8.4Hz), 4.87-4.96(m, 1H), 4.70(s, 1H), 4.67(s, 1H), 4.30(s, 1H), 4.28(s,1H), 3.92(t, 1H, J=5.6 Hz), 3.82(t, 1H, J=5.6 Hz), 3.46(s, 1.8H),3.44(s, 1.2H), 2.98(t, 1H, J=5.6 Hz), 2.93(t, 1H, J=5.6 Hz), 2.71(s,3H), 1.73(d, 6H, J=7.6 Hz).LC-MS: (M+H)⁺=508.2.

Embodiment 8

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), aqueous formaldehyde(20 mg), sodium triacetoxyborohydride (128 mg) were added to 3 mLdioxane, the mixture was stirred at room temperature for 12 hours. Thereaction solution was concentrated and purified by silica gel columnchromatography (dichloromethane/methanol 0 to 10%) to giveN-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzoimidazol-5-yl)pyrimidin-2-yl)-6-methyl-7,8-dihydro-5H-1,6-naphthyridin-2-aminerepresented by formula I-8 (40 mg, 0.08899 mmol). ¹H-NMR (400 MHz,CD₃OD) δ 8.54(d, 1H, J=4 Hz), 8.33(d, 1H, J=1.2 Hz), 8.22(d, 1H, J=8.4Hz), 7.52(d, 1H, J=8.4 Hz), 4.85-4.96(m, 1H), 3.75(s, 2H), 2.98-3.03(m,4H), 2.71(s, 3H), 2.59(s, 3H), 1.33(d, 6H, J=7.2 Hz). LC-MS: m/z:(M+H)⁺=450.2.

Embodiment 9

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), 3-hydroxypropionicacid (18 mg, 0.1998 mmol), HOBt (25 mg, 0.18502 mmol), EDCI (36 mg,0.18779 mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give1-(2-((5-fluoro-4-(7-fluoro-3sopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-3-hydroxyacetone(8 mg, 0.01576 mmol). ¹H-NMR (400 MHz, DMSO-d6) δ 10.05(d, 1H, J=10 Hz),8.70(d, 1H, J=4 Hz), 8.32(s, 1H), 8.13(m, 1H), 7.71(d, 1H, J=12.4 Hz),7.60-7.63(m, 1H), 4.83-4.89(m, 1H), 4.69(s, 1H)), 4.62(s, 1H),3.81-3.83(m, 2H), 3.68-3.69(m, 2H), 2.91(t, 1H, J=5.6 Hz), 2.80(t, 1H,J=5.6 Hz), 2.66(s, 3H), 2.60-2.63(m, 2H). LC-MS: m/z: (M+H)⁺=508.2.

Embodiment 10

Step 1:

N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(80 mg, 0.1837 mmol) (represented by formula I-1), pyridine (120 mg,1.517 mmol), methyl oxalyl chloride (50 mg, 0.40813 mmol) (representedby formula I-10-a) were added to 10 mL THF and the mixture was stirredat room temperature for 12 hours. The reaction solution was concentratedand purified by silica gel column chromatography(dichloromethane/methanol 0 to 10%) to give methyl2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-(2-methoxy-2-oxoacetyl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-oxoacetaterepresented by formula I-10-b (100 mg, 0.1646 mmol). LC-MS: m/z:(M+H)⁺=608.2.

Step 2:

Methyl2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-(2-methoxy-2-oxoacetyl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-oxoacetate(100 mg, 0.1646 mmol) (represented by formula I-10-b), lithium hydroxide(40 mg) and water (0.5 mL) were added to 3 mL methanol and the mixturewas stirred at room temperature for 12 hours. The reaction solution wasconcentrated and purified by silica gel column chromatography(dichloromethane/methanol 0 to 10%) to give methyl2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)pyrimidin-2-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-2-oxoacetaterepresented by formula I-10(70 mg, 0.1342 mmol). ¹H-NMR (400 MHz,DMSO-d₆) δ 10.10(d, 1H, J=7.2 Hz), 8.69(d, 1H, J=4 Hz), 8.32(d, 1H,J=1.2 Hz), 8.14-8.18(m, 1H), 7.61-7.72(m, 2H), 4.82-4.89(m, 1H), 4.68(s,1H), 4.60(s, 1H), 3.87-3.88(m, 4H), 3.75(t, 1H, J=5.6 Hz), 2.88-2.92(m,2H), 2.65(s, 3H), 1.64(d, 6H, J=6.8 Hz). LC-MS: m/z: (M+H)⁺=522.2.

Embodiment 12

N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(80 mg, 0.18 mmol) (represented by formula I-1), 2,2,2-trifluoroethylmethanesulfonate (60 mg, 0.26 mmol) and diisopropylethylamine (60 mg,0.46 mmol) were dissolved in N,N -dimethylformamide (3 mL) and themixture was stirred at 90° C. for 16 hours. Then the reaction solutionwas cooled to room temperature and filtered, the residue was dissolvedin dichloromethane, treated with ultrasound for 30 minutes, filtered,rinsed with dichloromethane, and the residue was dissolved in methanol,treated with ultrasound for 30 minutes, then filtered to giveN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminerepresented by formula I-12 (45 mg) as a pale yellow solid. ¹H-NMR (400MHz, DMSO-d₆) δ 9.97(s, 1H), 8.68 (d, 1H, J=4.0 Hz), 8.31 (d, 1H, J=1.2Hz), 8.08 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=12.4 Hz), 7.48 (d, 1H, J=8.4Hz), 4.83-4.88 (m, 1H), 3.82 (s, 2H), 3.40 (q, 2H, J=10.4 Hz), 3.04(t,2H, J=6.0 Hz), 2.86 (t, 2H, J=6.0 Hz), 2.66 (s, 3H), 1.64 (d, 6H, J=6.8Hz). LC-MS: m/z: (M+H)⁺=518.2

Embodiment 13

Step 1:

6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole(100 mg, 0.31 mmol) (represented by formula 1-c), tert-butyl2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylate (100 mg, 0.4mmol) (represented by formula I-13-a),tris(dibenzylideneacetone)dipalladium (50 mg, 0.05 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg, 0.05 mmol) andcesium carbonate (326 mg, 1 mmol) were dissolved in 1,4-dioxane (6 mL)and the mixture was stirred under argon atmosphere at 100° C. for 18hours. Then the reaction solution was concentrated and purified bycolumn chromatography (dichloromethane/methanol: 0% to 10%) to givetert-butyl2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate(45 mg) as pale yellow solid. LC-MS: (M+H)⁺=537.2.

Step 2:

Tert-butyl2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate(45 mg, 0.08 mmol) (represented by formula I-13-b) was dissolved intetrahydrofuran (2 mL), hydrochloric acid (4M) in tetrahydrofuran wasadded, the mixture was stirred at room temperature for 1 hour, thenconcentrated to giveN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-hydrobenzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-aminehydrochloride (40 mg) represented by I-13 as a pale yellow solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 10.67(s, 1H), 9.59 (s, 1H), 8.78 (d, 1H, J=3.6 Hz),8.53 (s, 1H), 8.39 (s, 1H), 7.92 (d, 1H, J=11.6 Hz), 4.90-4.94 (m, 1H),4.29 (t, 2H, J=4.8 Hz), 3.51 (q, 2H, J=6.0 Hz), 3.06 (t, 2H, J=6.4 Hz),2.75 (s, 3H), 1.65 (d, 6H, J=6.8 Hz). LC-MS m/z:(M+H)⁺=437.2.

Embodiment 14

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-aminehydrochloride (30 mg, 0.06 mmol) (represented by formula I-13),N,N-dimethylglycine (8 mg, 0.08 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg, 0.16mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) anddiisopropylacetamide (100 mg, 0.78 mmol) were dissolved in 1,4-dioxane(4 mL) and the mixture was stirred at room temperature for 16 hours.Then the reaction solution was concentrated, purified with TLC(DCM/CH₃OH=10/1), followed by column chromatography (C18, H₂O/CH₃OH=100%to 5%) to give2-dimethylamino-1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetamiderepresented by formula I-14(9 mg) as pale yellow solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.54-8.55(m, 1H), 8.44 (s, 1H), 8.22-8.25 (m, 1H), 8.15 (s,1H), 7.90-7.95 (m, 1H), 4.73-4.85 (m, 3H), 3.97 (t, 2H, J=6.0 Hz),3.24-3.26 (m, 2H), 2.98-3.08 (m, 2H), 2.72 (s, 3H), 2.30-2.33 (m, 6H),1.73 (d, 6H, J=6.8 Hz). LC-MS: m/z: (M+H)⁺=522.3.

Embodiment 15

Step 1:

6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-benzimidazole(500 mg, 1.55 mmol) (represented by formula 1 -c), aqueous ammonia (5mL, 35%) and 1,4-dioxane (5 mL) were added to a sealed tube and themixture was stirred at 100° C. for 16 hours, then concentrated anddiluted with dichloromethane (30 mL). After 30 minutes under ultrasound,the mixture was filtered, and the residue was rinsed withdichloromethane and dried to give5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-aminerepresented by formula I-15-a (280 mg, 0.92 mmol) as a pale yellowsolid. LC-MS m/z: (M+H)⁺=304.2.

Step 2:

2-Chloro-6-(2-(dimethylamino)ethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(40 mg, 0.17 mmol) (represented by formula 2-g),5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2-amine(60 mg, 0.19 mmol) (represented by formula I-15-a),tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.04 mmol) andcesium carbonate (120 mg, 0.37 mmol) were dissolved in 1,4-dioxane (6mL) and the mixture was stirred under argon atmosphere at 100° C. for 18hours, then concentrated and purified by column chromatography(dichloromethane/methanol 0% to 10%) to give6-(2-(dimethylamino)ethyl)-2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(45 mg, 0.09 mmol) represented by formula I-15 as a pale yellow solid.¹H-NMR (400 MHz, CDCl₃) δ 8.62(d, 1H, J=8.8 Hz), 8.44 (s, 1H), 8.50 (d,1H, J=3.6 Hz), 8.40 (s, 1H), 8.24 (d, 1H, J=1.2 Hz), 8.09 (d, 1H, J=11.6Hz), 7.80 (d, 1H, J=11.6 Hz), 4.74-4.79 (m, 1H), 4.53 (s, 2H), 3.89 (t,2H, J=7.8 Hz), 2.86 (t, 2H, J=6.4 Hz), 2.72 (s, 3H), 2.51 (s, 6H), 1.75(d, 6H, J=6.8 Hz). LC-MS m/z: (M+H)⁺=507.9

Embodiment 17

Step 1:

N-(5-fluoro-4-(7-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(80 mg, 0.18 mmol) (represented by formula I-1), N-boc-glycine (39 mg,0.22 mmol) (represented by formula I-17-a), HOBt (30 mg, 0.22 mmol),EDCI (42 mg, 0.22 mmol) were added to 1 mL DMF and the mixture wasstirred at room temperature for 12 hours. The reaction solution wasconcentrated and purified by silica gel column chromatography(dichloromethane/methanol 0-10%) to give the compound represented byformula I-17-b as a yellow solid 43 mg, yield 39%. ¹H-NMR (400 MHz,CDCl₃) δ 8.45 (d, 1H, J=3.6 Hz), 8.34 (dd, 1H, J=8.5, 3.3 Hz), 8.17-8.21(m, 2H), 7.79 (d, 1H, J=11.7 Hz), 7.48 (d, 0.66H, J=8.6 Hz), 7.43(d,0.44H, J=8.6 Hz), 5.57 (s, 1H), 4.76(s, 1H), 4.71-4.79(m, 1H), 4.56(s,1H), 4.10(t, 2H, J=3.2 Hz), 3.98 (t, 1H, J=6.0 Hz), 3.75 (t, 1H, J=5.9Hz), 3.00(t, 1H, J=6.0 Hz), 2.96(t, 1H, J=6.0 Hz), 2.71 (s, 3H), 1.73(d, J=6.9 Hz, 6H), 1.48 (s, 9H). LC-MS: m/z: (M+H)⁺=593.2.

Step 2:

Tert-butyl(2-(2-((5-Fluoro-4-)7-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol--yl)pyridin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-oxoethyl)carbamate(43 mg, 0.23 mmol) (represented by formula I-17-b) was dissolved in 5 mLdioxane, 4N HCl in dioxane (1 mL) was added dropwise, and the mixturewas stirred at room temperature for 4 hours. The solvent was evaporatedunder reduced pressure, saturated sodium bicarbonate solution was added,and the mixture was extracted with dichloromethane. The solvent wasevaporated under reduced pressure to give 21 mg the compound representedby formula I-17 as a yellow solid, yield 59%. ¹H-NMR (400 MHz, CD₃OD) δ8.94 (s, 1H), 8.58 (s, 1H), 8.20 (t, 2H, J=9.3 Hz), 7.56 (d, 1H, J=8.8Hz), 5.14-5.15 (m, 1H), 4.78 (s, 2H), 4.17(s, 1H), 4.14(s, 1H), 4.08(s,1H), 3.92(s, 1H), 3.24 (s, 2H), 2.97 (s, 3H), 1.83 (d, 6H, J=6.9 Hz).LC-MS: m/z: (M+H)⁺=493.2.

Embodiment 19

N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(200 mg, 0.46 mmol) (represented by formula I-1), methyl bromoacetate(281 mg, 1.837 mmol), N,N-diisopropylethylamine (178 mg) were added to10 mL 1,4-dioxane, and the mixture was stirred at 90° C. for 12 hours.The reaction solution was concentrated and purified by silica gel columnchromatography (dichloromethane/methanol 0 to 10%) to give methyl2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetaterepresented by formula I-19 (130 mg, 0.256 mmol). ¹H-NMR (400 MHz,CD₃OD) δ 8.53 (d, J=3.9 Hz, 1H), 8.32 (s, 1H), 8.16 (d, J=8.5 Hz, 1H),7.75 (d, J=12.2 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 4.89-4.95(m, 1H),3.77-3.81(m, 2H), 3.78(s, 3H), 3.62(s, 0.5H), 3.51(s, 1.5H),2.97-3.02(m, 4H), 2.70(s, 3H), 1.73 (d, 6H, J=6.9 Hz). LC-MS m/z:(M+H)⁺=508.2.

Embodiment 20

Methyl2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (100 mg, 0.197mmol) (represented by formula I-19), LiOH (42 mg), H₂O (10 mL) wereadded to MeOH (10 mL), the mixtured was stirred at 75° C. for 1 hour.The reaction solution was filtered and washed to give2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)aceticacid represented by formula I-20 (70 mg, 0.14 mmol). ¹H-NMR (400 MHz,DMSO-d₆) δ 10.00 (s, 1H), 8.69 (d, J=4.3 Hz, 1H), 8.32 (s, 1H), 8.09 (d,J=8.7 Hz, 1H), 7.71 (d, J=11.7 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H),4.83-4.88 (m, 1H), 3.87 (s, 2H), 3.04 (s, 2H), 2.90 (s, 2H), 2.66 (s,3H), 2.00-2.04(m, 2H), 1.64 (s, 6H, 6.8 Hz). LC-MS: m/z: (M+H)⁺=495.2.

Embodiment 21

Tert-butyl2-((4-(1-Cyclopentyl-7-fluoro-2-methyl-1H-benzo[d]imidazol-5-yl)-5-fluoropyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate(340 mg, 0.61 mmol) (represented by formula 3-d) were dissolved in 5 mLdioxane, 4N HCl in dioxane (1 mL) was added dropwise and the mixture wasstirred at room temperature for 4 hours. Solvent was evaporated underreduced pressure, saturated sodium bicarbonate solution was added, themixture was extracted with dichloromethane, and the solvent wasevaporated under reduced pressure to give 230 mg the compoundrepresented by formula I-21 as a yellow solid, yield 82%. ¹H-NMR (400MHz, DMSO-d₆) δ 9.83 (s, 1H), 8.67 (d, 1H, J=3.8 Hz), 8.12 (s, 1H), 8.02(d, 1H, J=7.6 Hz), 7.73 (d, 1H, J=12.1 Hz), 7.39-7.45 (m, 1H), 5.06-4.90(m, 1H), 4.41 (s, 1H), 3.82 (s, 1H), 3.58 (s, 1H), 3.18 (s, 2H), 3.03(s, 1H), 2.66 (s, 3H), 2.11-2.20 (m, 4H), 1.96-2.01 (m, 2H), 1.83-1.69(m, 2H). LC-MS: m/z: (M+H)⁺=461.9.

Embodiment 22

Step 1:

N-(5-Fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl]-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(90 mg, 0.195 mmol) (represented by formula I-21), N-boc-sarcosine (46mg, 0.24312 mmol), HOBt (25 mg, 0.18502 mmol), EDCI (36 mg, 0.18779mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give tert-butylN-(2-(2-((5-fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2-oxoethyl)-N-methyl-carbamaterepresented by formula I-22-a (100 mg, 0.158 mmol).

Step 2:

Tert-butylN-(2-(2-((5-fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2-oxoethyl)-N-methyl-carbamate(100 mg, 0.158 mmol) (represented by formula I-22-a) was add to 2MHCl/MeOH solution (2 mL) and the mixture was stirred at room temperaturefor 1 hour, then concentrated to give1-(2-((5-fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazole-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-(methylamino)ethanonerepresented by formula I-22-b (70 mg, 0.1314 mmol).

Step 3:

1-(2-((5-Fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazole-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-(methylamino)ethanone(70 mg, 0.1314 mmol) (represented by formula I-22-b), aqueousformaldehyde (30 mg) and sodium triacetoxyborohydride (128 mg) wereadded to 3 mL dioxane and the mixture was stirred at room temperaturefor 12 hours. The reaction solution was concentrated and purified bysilica gel column chromatography (dichloromethane/methanol 0 to 10%) togive2-(dimethylamino)-1-(2-((5-fluoro-4-(7-fluoro-3-cyclopentyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)ethanonerepresented by formula I-22 (40 mg, 0.08899 mmol). ¹H-NMR (CD₃OD) δ=8.50(d, 1H, J=3.6 Hz), 8.23-8.27 (m, 1H), 8.17 (s, 1H), 7.77-7.80 (m, 1H),7.55 (d, 1H, J=8.4 Hz), 4.96-5.02 (m, 2H), 4.77 (s, 1H), 4.70 (s, 1H),3.90-3.94 (m, 2H), 2.90-3.01 (m, 2H), 2.70 (s, 3H), 2.35 (s, 4H), 2.33(s, 2H), 2.27 (s, 4H), 2.06-2.09 (m, 2H), 1.87-1.90 (s, 2H). LC-MS:m/z(M+H)⁺=547.2.

Embodiment 23

N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine (80 mg,0.1837 mmol) (represented by formula I-1), 4-methyl-1-piperazine aceticacid (32 mg, 0.20 mmol), HOBt (25 mg, 0.18502 mmol), EDCI (36 mg,0.18779 mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-(4-methylpiperazin-1-yl)ethanone(60 mg, 0.104 mmol). ¹H-NMR (DMSO-d₆) δ 9.99-10.02 (m, 1H), 8.69 (d, 1H,J=4 Hz), 8.30 (s, 1H), 8.11-8.16 (m, 1H), 7.70 (d, 1H, J=12 Hz),7.55-7.72 (m, 1H), 4.81-4.89 (m, 1H), 4.75 (s, 1H), 4.60 (s, 1H),3.77-3.88 (m, 2H), 3.23-3.25 (m, 2H), 2.90-2.95 (m, 1H), 2.65 (s, 3H),2.33-2.43 (m, 6H), 2.16 (s, 2H), 2.09 (s, 1H), 1.64 (d, 6H, J=6.8 Hz).LC-MS: m/z (M+H)⁺=576.2.

Embodiment 26

N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(represented by formula I-1) (80 mg, 0.1837 mmol),3-hydroxy-3-methylbutyric acid (28 mg, 0.237 mmol), HOBt (25 mg, 0.18502mmol), EDCI (36 mg, 0.18779 mmol) were added to 1 mL DMF and the mixturewas stirred at room temperature for 12 hours. The reaction solution wasconcentrated and purified by silica gel column chromatography(dichloromethane/methanol 0 to 10%) to give1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-3-hydroxy-3-methyl-butanonerepresented by formula I-26 (10 mg, 0.019 mmol). ¹H-NMR (DMSO-d₆) δ10.06 (d, 1H, J=11.2 Hz), 8.70 (d, 1H, J=4 Hz), 8.32 (s, 1H), 8.12-8.15(m, 1H), 7.70 (d, 1H, J=12 Hz), 7.57-7.63 (m, 1H), 4.81-4.87 (m, 2H),4.73 (s, 1H), 4.65 (s, 1H), 3.82-3.88 (m, 2H), 2.89-2.92 (m, 1H),2.79-2.82 (m, 1H), 2.66 2.57-2.59 (m, 3H), 1.64 (d, 6H, J=6.8 Hz), 1.21(s, 3H), 1.19 (s, 3H). LC-MS: m/z (M+H)⁺=536.2.

Embodiment 27

Step 1:

N-(5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (110 mg,0.25 mmol) (represented by formula I-1),N-tert-butoxycarbonyl-2-methylalanine (100 mg, 0.49 mmol), EDCI (60 mg,0.31 mmol), HOBt (40 mg, 0.29 mmol) and diisopropylacetamide (500 mg,3.87 mmol) were dissolved in DMF (4 mL) and the mixture was stirred atroom temperature for 16 hours. The reaction solution was concentratedand purified by silica gel column chromatography (DCM/CH₃OH 0 to 10%) togive tert-butyl(1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)2-methyl-1-oxopropan-2-yl)carbamaterepresented by formula I-27-a (70 mg) as a pale yellow solid. LC-MS m/z:(M+H)⁺=621.1.

Step 2:

Tert-butyl(1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)2-methyl-1-oxopropan-2-yl)carbamate (70 mg, 0.11 mmol)(represented by formula I-27-a) was dissolved in 1,4-dioxane (4 mL), asolution of hydrochloride (4M) in 1,2-dioxane was added, then themixture was stirred at room temperature for 16 hours, filtered, the cakewas dissolved in water. After adjusting the pH to 7 by adding aqueoussodium bicarbonate solution, the mixture was extracted with a mixedsolution of dichloromethane and methanol, and the organic layer wasconcentrated to give2-amino-1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-methylpropyl-1-onerepresented by formula I-27-b (40 mg). LC-MS m/z: (M+H)⁺=521.2.

Step 3:

2-Amino-1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-methylpropyl-1-one(40 mg, 0.077 mmol) (represented by formula I-27-b) was dissolved indioxane (4 mL), aqueous formaldehyde solution (10 mg, 0.33 mmol) wasslowly added dropwise and the mixture was stirred at room temperaturefor 1 hour, then sodium triacetoxyborohydride (60 mg, 0.28 mmol) wasadded and stirred for 16 hours. The reaction was quenched with water,then aqueous sodium bicarbonate was added to adjust the pH to 7, themixture was extracted with dichloromethane, the organic layer was driedover anhydrous sodium sulfate, and purified by thin-layer chromatography(DCM/CH₃OH=10/1) to give a crude product, which was dissolved indimethyl sulfoxide, filtered, and the residue was rinsed with methanoland dried to give2-(methylamino)-1-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-hydrobenzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-2-methylpropyl-1-one(15 mg) as a yellow solid. ¹H-NMR (CDCl₃) δ 8.44 (d, 1H, J=4.0 Hz), 8.29(d, 1H, J=6.8 Hz), 8.22 (s, 1H), 7.92-8.01(m, 1H), 7.81 (d, 1H, J=11.6Hz), 7.42-7.50 (m, 1H), 5.40-5.44 (m, 1H), 4.73-4.81 (m, 2H), 4.51-4.54(m, 1H), 3.96-3.98 (m, 1H), 2.96 (t, 2H, J=4.4 Hz), 2.72 (s, 3H),2.18-2.26 (m, 6H), 1.74 (d, 6H, J=7.2 Hz), 1.28-1.32 (m, 6H). LC-MS m/z:(M+H)⁺=548.9.

Embodiment 28

Tert-butyl2-((5-fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate(7 g, 13.1 mmol) was dissolved in dioxane (40 mL) and a solution ofhydrochloric acid (2M, 30 mL) in dioxane was added, the mixture wasstirred at room temperature for 16 hours, concentrated, and slurriedwith dichloromethane to giveN-(5-fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazole-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminohydrochloride represented by formula I-28 (5.5 g). ¹H-NMR (DMSO-d₆) δ11.0 (s, 1H), 10.0 (s, 2H), 8.87 (d, 1H, J=3.2 Hz), 8.29(s, 1H), 8.08(d, 1H, J=8.8 Hz), 7.92-7.95 (m, 2H), 4.29 (s, 2H), 3.55-3.60 (m, 1H),3.46-3.49 (m, 2H), 3.19 (t, 2H, J=6.0 Hz), 2.82 (s, 3H), 1.31-1.36 (m,2H), 1.20-1.22 (m, 2H). LC-MS m/z: (M+H)⁺=434.2.

Embodiment 29

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(100 mg, 0.25 mmol) (represented by formula I-28), N,N-dimethylglycine(100 mg, 0.49 mmol), EDCI (60 mg, 0.31 mmol), HOBt (40 mg, 0.29 mmol)and diisopropylacetamide (500 mg, 3.87 mmol) were dissolved in a mixedsolution of DMF (4 mL) and dichloromethane (4 mL) and the mixture wasstirred at 60° C. for 16 hours. The reaction solution was concentratedand purified by silica gel column chromatography(DCM/CH₃OH/NH₃.CH₃OH=100/10/1) to give(1-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5 -yl)-5-fluoro-pyrimidin-2-yl)amino-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2-(dimethylamino)-ethanonerepresented by formula I-29 (70 mg) as a pale yellow solid. ¹H-NMR(CDCl₃+CD₃OD) δ 8.37 (s, 1H), 8.23 (d, 1H, J=8.0 Hz), 8.11 (s, 1H),7.72(d, 1H, J=11.2 Hz), 7.44-7.46 (m, 1H), 4.64-4.67 (m, 2H), 3.82-3.85(m, 2H), 3.25-3.31 (m, 4H), 2.86-2.92 (m, 2H), 2.66 (s, 3H), 2.31 (s,6H), 1.28-1.35 (m, 2H), 1.08-1.10 (m, 2H). LC-MS m/z: (M+H)⁺=519.2.

Embodiment 30

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (100 mg, 0.25 mmol) (represented by formula I-28),N,N-morpholin-4-yl acetic acid (100 mg, 0.49 mmol), EDCI (60 mg, 0.31mmol), HOBt (40 mg, 0.29 mmol) and diisopropylacetamide (500 mg, 3.87mmol) were dissolved in DMF (4 mL) and the mixture was stirred at roomtemperature for 16 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (DCM/CH₃OH=100% to 90%) togive(1-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl))-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2-morpholine-ethanonerepresented by formula I-30 (20 mg) as a pale yellow solid. ¹H-NMR(CDCl₃) δ 8.44-8.46 (m, 1H), 8.30-8.33 (m, 1H), 8.16-8.18 (m, 1H), 8.09(s, 1H), 7.78-7.82(m, 1H), 7.50-7.52 (m, 1H), 4.74-4.79 (m, 2H),3.92-3.95 (m, 2H), 3.75-3.77 (m, 2H), 3.67-3.72 (m, 1H), 3.31-3.35 (m,3H), 2.94-3.05 (m, 2H), 2.76 (s, 3H), 2.55-2.57 (m, 4H), 1.33-1.38 (m,2H), 1.13-1.17 (m, 2H). LC-MS m/z: (M+H)⁺=561.2.

Embodiment 31

3-Hydroxycyclobutylcarboxylic acid (26 mg, 0.22391 mmol),N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(80 mg, 0.1837 mmol) (represented by formula I-28),1-hydroxybenzotriazole (25 mg, 0.185 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg,0.18779 mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-(3-hydroxycyclobutyl)methanone(50 mg, 0.09370 mmol). ¹H-NMR (DMSO-d₆) δ 10.05 (d, 1H, J=12 Hz), 8.69(d, 1H, J=3.6 Hz), 8.32 (s, 1H), 8.13 (d, 1H, J=8.4 Hz), 7.71 (d, 1H,J=12.4 Hz), 7.60 (d, 1H, J=16.4 Hz), 5.07 (s, 1H), 4.84-4.88 (m, 1H),4.57-4.61 (m, 2H), 3.99 (s, 1H), 3.71-3.81 (m, 2H), 2.83-2.90 (m, 3H),2.68 (s, 3H), 2.38-2.42 (m, 2H), 1.93-2.03 (m, 2H), 1.64 (d, 6H, J=6.8Hz). LC-MS: m/z: (M+H)⁺=534.2.

Embodiment 32

3-Hydroxycyclobutylcarboxylic acid (26 mg, 0.22391 mmol),N-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(80 mg, 0.1837 mmol) (represented by formula I-28),1-hydroxybenzotriazole (25 mg, 0.185 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36 mg,0.18779 mmol) were added to 1 mL DMF and the mixture was stirred at roomtemperature for 12 hours. The reaction solution was concentrated andpurified by silica gel column chromatography (dichloromethane/methanol 0to 10%) to give(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-(3-hydroxycyclobutyl)methanone(50 mg, 0.09370 mmol). ¹H-NMR (DMSO-d₆) 10.05 (d, 1H, J=12 Hz), 8.69 (d,1H, J=3.6 Hz), 8.32 (s, 1H), 8.13 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=12.4Hz), 7.60 (d, 1H, J=16.4 Hz), 5.07 (s, 1H), 4.84-4.88 (m, 1H), 4.57-4.61(m, 2H), 3.99 (s, 1H), 3.71-3.81 (m, 2H), 2.83-2.90 (m, 3H), 2.68 (s,3H), 2.38-2.42 (m, 2H), 1.93-2.03 (m, 2H), 1.64 (d, 6H, J=6.8 Hz).LC-MS: m/z: (M+H)⁺=534.2.

Embodiment 37

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(100 mg, 0.23 mmol) (represented by formula I-28),2-bromo-N,N-dimethylacetamide (50 mg, 0.30 mmol), diisopropylacetamide(200 mg, 1.55 mmol) were dissolved in DMF (2 mL) and the mixture wasstirred at 90° C. for 16 hours. The reaction solution was cooled anddiluted with water, extracted with ethyl acetate. The organic layer wasconcentrated and purified by silica gel thin-layer chromatography(DCM/CH₃OH=10/1). The crude product was slurried with ethyl acetate togive(2-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-acetamiderepresented by formula I-37 (5 mg) as a pale yellow solid.

¹H-NMR (CDCl₃) δ 8.43 (d, 1H, J=3.6 Hz), 8.23 (d, 1H, J=8.4 Hz), 8.19(s, 1H), 8.06 (s, 1H), 7.80(d, 1H, J=12.0 Hz), 7.40(d, 1H, J=8.0 Hz),3.75 (s, 2H), 3.43 (s, 2H), 3.32-3.33 (m, 1H), 3.15 (s, 3H), 2.96-3.01(m, 6H), 2.76 (s, 3H), 1.33-1.38 (m, 2H), 1.13-1.17 (m, 2H). LC-MS m/z:(M+H)⁺=519.2.

Embodiment 52

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(1 g, 2.3 mmol) (represented by formula I-28),2-(dimethylamino)acetaldehyde (600 mg, 6.9 mmol) were dissolved indichloromethane, sodium triacetoxyborohydride (1.5 g, 7.1 mmol) wasslowly added, and the mixture was stirred under reflux for 16 hours. Thereaction solution was concentrated and purified by silica gel columnchromatography (DCM/CH₃OH/NH₃.CH₃OH=100/10/2) to giveN-(4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)6-(2-dimethylaminoethyl)-7,8-dihydro-5H-1,6-naphthyridin-2-aminerepresented by formula I-52 (1.1 g) as a pale yellow solid. ¹H-NMR(CDCl₃) δ 8.43 (d, 1H, J=3.6 Hz), 8.26 (d, 1H, J=8.8 Hz), 8.19 (s, 1H),7.80(d, 1H, J=11.6 Hz), 7.42(d, 1H, J=8.4 Hz), 3.72 (s, 2H), 3.31-3.34(m, 1H), 3.10(t, 2H, J=6.4 Hz), 2.92-2.98 (m, 6H), 2.76 (s, 3H), 2.74(s, 6H), 1.33-1.38 (m, 2H), 1.13-1.17 (m, 2H). LC-MS m/z: (M+H)⁺=505.2.

Embodiment 61

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(100 mg, 0.23 mmol) (represented by formula I-28),bis(trichloromethyl)carbonate (40 mg, 0.13 mmol) and DIPEA (120 mg, 0.93mmol) were dissolved in dichloromethane and the mixture was stirred atroom temperature for 1 hour, then N,N,N′-trimethylethylenediamine (50mg, 0.49 mmol) was added and stirred at room temperature for 16 hours.The reaction solution was concentrated, diluted with dichloromethane andwater, partitioned, and the aqueous layer was concentrated and purifiedby column chromatography (C18, H₂O/CH₃OH=100% to 90%) and then purifiedby thin layer chromatography (DCM/CH₃OH=10/1) to give2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidine-)2-yl)amino)-N-(2-dimethylaminoethyl)-N-methyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamiderepresented by formula I-61 (10 mg) as a pale yellow solid. ¹H-NMR (400MHz, CD₃OD) δ 8.45 (d, 1H, J=4.4 Hz), 7.93 (d, 1H, J=8.0 Hz), 7.79 (s,1H), 7.43(d, 1H, J=12.0 Hz), 7.27(d, 1H, J=8.0 Hz), 4.28 (s, 2H),3.52-3.55 (m, 4H), 3.24-3.27(m, 1H), 3.04-3.07 (m, 5H), 2.80-8.83 (m,2H), 2.72 (s, 6H), 2.58 (s, 3H), 1.22-1.24 (m, 2H), 0.95-0.98 (m, 2H).LC-MS m/z: (M+H)⁺=562.3.

Embodiment 62

Step 1:

N-(5 -fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(110 mg, 0.23 mmol) (represented by formula I-1), Boc-N-methyl-D-alanine(60 mg, 0.29 mmol), EDCI (60 mg, 0.31 mmol), HOBt (50 mg, 0.37 mmol) anddiisopropylacetamide (100 mg, 0.77 mmol) were dissolved in DMF (4 mL)and the mixture was stirred at room temperature for 16 hours. Thereaction solution was purified by silica gel column chromatography(DCM/CH₃OH 0 to 10%) to givetert-butylN-((1R)-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-1-methyl-2-oxo-ethyl)-N-methylcarbamaterepresented by formula I-62-a (130 mg) as a pale yellow solid. LC-MSm/z: (M+H)⁺=607.2.

Step 2:

Tert-butylN-((1R)-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-1-methyl-2-oxo-ethyl)-N-methylcarbamate(120 mg, 0.19 mmol)(represented by formula I-62-a) was dissolved in1,4-dioxane (4 mL), a solution of hydrochloride (4M) in 1,2-dioxane wasadded, the mixture was stirred at room temperature for 16 hours,filtered, dissolved in water. After adjusting the pH to 7 by addingaqueous sodium bicarbonate solution, the mixture was extracted with amixed solution of dichloromethane and methanol, and the organic solventwas concentrated to give(2R)-1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6-yl)-2-(methylamino)propyl-1-onerepresented by the formula I-62-b (110 mg). LC-MS m/z: (M+H)⁺=507.2.

Step 3:

(2R)-1-(2-((5-Fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6-yl)-2-(methylamino)propyl-1-one(110 mg, 0.21 mmol) (represented by the formula I-62-b) was dissolved inmethanol (4 mL), aqueous formaldehyde solution (10 mg, 0.33 mmol) wasslowly added dropwise and the mixture was stirred at room temperaturefor 1 hour, then sodium cyanoborohydride (50 mg, 0.44 mmol) was addedand stirred for 16 hours. The reaction solution was concentrated andpurified by column chromatography (DCM/CH₃OH/NH₃.CH₃OH=10/1/0.2) to givea crude product, which was then purified by preparative liquidchromatography to give(2R)-2-(methylamino)-1-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)propyl-1-ketonerepresented by formula I-62 (30 mg) as a yellow solid. ¹H-NMR (400 MHz,CD₃OD) δ 8.55 (d, 1H, J=3.6 Hz), 8.33 (d, 1H, J=1.2 Hz), 8.28 (t, 1H,J=7.2 Hz), 7.80(d, 1H, J=12.0 Hz), 7.61-7.64 (m, 1H), 4.88-4.96 (m, 2H),4.66-4.75 (m, 1H), 4.45-4.49 (m, 1H), 3.85-4.11 (m, 2H), 3.03-3.11 (m,1H), 2.95-2.98 (m, 1H), 2.84 (d, 6H, J=3.6 Hz), 2.71 (s, 3H), 1.74 (d,6H, J=6.8 Hz), 1.50-1.56 (m, 3H). LC-MS m/z: (M+H)⁺=535.2.

Embodiment 72

Step 1:

N-(5-Fluoro-4-(7-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(200 mg, 0.46 mmol) (represented by formula I-1) was dissolved in 5 mLmethanol, 1-tert-butoxycarbonyl-3-pyrrolidone (170 mg, 0.92 mmol) andsodium triacetoxyborohydride (146 mg, 0.92 mmol) were added, the mixturewas stirred at room temperature for 16 hours. Solvent was evaporatedunder reduced pressure, saturated sodium bicarbonate solution was added,the mixture was extracted with dichloromethane, evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the compound represented by formula I-72-a as a yellow solid(170 mg), yield 61%.LC-MS: 604.9 [M+H]⁺.

Step 2:

Tert-butyl3-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)pyrrolidine-1-carboxylate(represented by formula I-72-a) (170 mg, 0.28 mmol) was dissolved in 5mL dioxane, a solution of 4N HCl in dioxane (1 mL) was added dropwise,and the mixture was stirred at room temperature for 4 hours. Solvent wasevaporated under reduced pressure, saturated sodium bicarbonate solutionwas added, and the mixture was extracted with dichloromethane. Thesolvent was evaporated under reduced pressure to give the compoundrepresented by the formula I-72-b as a yellow solid (138 mg), yield 97%.LC-MS: 504.9 [M+H]⁺.

Step 3:

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(pyrrolidine-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(represented by formula I-72-b) (138 mg, 0.27 mmol) was dissolved in 5mL dioxane, sodium hydroxide (55 mg, 1.37 mmol) and bromopropyne (32 mg,0.27 mmol) were added and the mixture was stirred at room temperaturefor 2 hours. Solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thecompound represented by formula I-72 as a yellow solid, 55 mg, 38%yield. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=3.8 Hz, 1H), 8.23 (dd,J=9.2, 4.8 Hz, 2H), 7.99 (s, 1H), 7.80 (d, J=12.2 Hz, 1H), 7.39 (d,J=8.5 Hz, 1H), 4.75 (dt, J=14.0, 7.0 Hz, 1H), 3.69 (s, 2H), 3.49 (d,J=2.2 Hz, 2H), 3.27-3.05 (m, 2H), 3.00 (d, J=7.9 Hz, 2H), 2.97-2.75 (m,4H), 2.74-2.68 (m, 3H), 2.28 (t, J=2.3 Hz, 1H), 2.20 (dd, J=13.0, 6.3Hz, 1H), 1.92 (dd, J=12.9, 6.4 Hz, 2H), 1.73 (d, J=7.0 Hz, 6H). LC-MS:m/z: (M+H)⁺=542.9.

Embodiment 73

Step 1:

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(100 mg, 0.23 mmol) (represented by formula I-28),2(R)-2-chloromethyloxirane (30 mg, 0.32 mmol) and DIPEA (100 mg, 0.77mmol) were dissolved in N,N-dimethylformamide (4 mL), the mixture wasstirred at 80° C. for 16 hours. The reaction solution was concentratedand purified by silica gel column chromatography (DCM/CH₃OH=10/1) togive(S)-N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(epoxy-2-ylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminerepresented by formula I-73-a (30 mg) as a pale yellow solid. LC-MS m/z:(M+H)⁺=490.2.

Step 2:

(S)-N-(4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)-6-(epoxy-2-ylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(30 mg,0.06 mmol) (represented by formula I-73-a), dimethylamine (10 mg,0.22 mmol) were dissolved in ethanol (5 mL), the mixture was stirred at60° C. for 4 hours. The reaction solution was concentrated and purifiedby silica gel column chromatography (DCM/CH₃OH=10/1) to give(S)-1-(2-((4-(1-cyclopropyl-4-fluoro-2-methyl-1H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-3-(dimethylamino)propyl-2-olrepresented by formula I-73 (10 mg) as a pale yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.37 (d, J=3.7 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.13 (s,1H), 7.77-7.70 (m, 1H), 7.40 (d, J=8.6 Hz, 1H), 4.35 (m, 1H), 3.77 (s,2H), 3.23 (d, J=15.2 Hz, 2H), 3.06-2.91 (m, 5H), 2.87 (s, 6H), 2.72-2.62(m, 5H), 1.34-1.29 (m, 2H), 1.10 (t, J=8.0 Hz, 2H). LC-MS m/z:(M+H)⁺=534.9.

Embodiment 77

Step 1:

N-(5-Fluoro-4-(7-fluoro-3-cyclopropyl-2-methyl-benzoimidazol-5-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(100 mg, 0.23 mmol) (represented by formula I-28), N-boc-D-alanal (100mg, 0.58 mmol) were dissolved in dichloromethane, sodiumtriacetoxyborohydride (200 mg, 0.94 mmol) was added slowly, the mixturewas stirred under reflux for 16 hours. The reaction solution wasconcentrated and purified by silica gel column chromatography(DCM/CH₃OH/NH₃.CH₃OH=100/10/2) to giveN-(4-(3-tert-butyl-N-((1R)-2-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-1-methyl-ethyl)carbonaterepresented by formula I-77-a (60 mg) as a pale yellow solid. LC-MS m/z:(M+H)⁺=591.2.

Step 2:

Tert-butyl N-((1R)-2-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidine2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)-1-methyl-ethyl)carbonate(60 mg, 0.2 mmol) (represented by formula I-77-a) was dissolved indichloromethane (4 mL), a solution of hydrochloric acid in 1,2-dioxane(4M, 1 mL) was added, and the mixture was stirred at room temperaturefor 4 hours. The reaction solution was concentrated and dissolved indichloromethane and stirred at room temperature for 30 min, thenfiltered and dried to give6-((2R)-aminopropyl)-N-(4-(3-cyclopropyl-7-fluoro-2-yl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-7,8-dihydro-5H-1,6-naphthyridin-2-aminohydrochloride (60 mg) as a pale yellow solid.

¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J=3.3 Hz, 1H), 8.58 (s, 1H), 8.27 (d,J=11.2 Hz, 1H), 8.22 (d, J=9.1 Hz, 1H), 7.59 (d, J=9.0 Hz, 1H),4.75-4.44 (m, 2H), 4.08 (M, 1H), 3.95-3.82 (m, 1H), 3.80-3.73 (m, 2H),3.67-3.48 (m, 4H), 3.04 (s, 3H), 1.54 (M, 5H), 1.42-1.34 (m, 2H). LC-MS:m/z: (M+H)⁺=490.9.

Embodiment 80

6-((2R)-Aminopropyl)-N-(4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidine-2-yl)-7,8-dihydro-5H-1,6-naphthyridin-2-amine(50 mg, 0.21 mmol) (represented by formula I-77) was dissolved inmethanol (6 mL), aqueous formaldehyde (20 mg, 0.67 mmol) was slowlyadded dropwise, followed by addition of sodium triacetoxyborohydride(50mg, 0.24 mmol), the mixture was stirred at 60° C. for 16 hours. Thereaction solution was concentrated and purified by column chromatography(DCM/CH₃OH/NH₃.CH₃OH=10/1/0.2) to give a crude product, which waspurified by preparative liquid phase to giveN-(4-(3-cyclopropyl-7-fluoro-2-methyl-benzoimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-6-((2R)-2-(dimethylaminopropyl)-7,8-dihydro-5H-1,6-naphthyridin-2-aminerepresented by formula I-80 (25 mg) as a pale yellow solid. ¹H NMR (400MHz, CD₃OD) δ 8.52 (d, J=3.9 Hz, 1H), 8.26 (s, 1H), 8.18 (d, J=8.5 Hz,1H), 7.80 (d, J=12.1 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 3.87 (d, J=14.7Hz, 1H), 3.78-3.65 (m, 2H), 3.46 (m, 1H), 3.14-3.04 (m, 1H), 3.02-2.88(m, 4H), 2.80 (s, 6H), 2.75 (s, 3H), 2.68 (m, 1H), 1.36 (d, J=7.0 Hz,2H), 1.31 (d, J=6.6 Hz, 3H), 1.21-1.14 (m, 2H). LC-MS: m/z: (M+H)⁺=519.0

Embodiment 95

Step 1:

Potassium carbonate (75 mg, 0.55 mmol) andN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(120 mg, 0.275 mmol) was added to 15 mL N,N -dimethylformamide, followedby the addition of ethyl bromoacetate (75 mg, 0.45 mmol), the mixturewas stirred at room temperature overnight. The reaction solution wasevaporated to dryness under reduced pressure and purified by silica gelcolumn chromatography to give2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethylacetate represented by the formula I-95-a (100 mg) as a pale yellowsolid.

Step 2:

Ethyl2-(2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate was dissolved in 15 mL dry dichloromethane, and 2 mL DIBAL-H (1mol/L in toluene) was added at −78° C., the mixture was stirred at thistemperature for 3 h. Then the reaction was quenched with methanol, 2 mLsaturated ammonium chloride was added and the mixture was stirred atroom temperature for 10 minutes. The organic layer was dried over sodiumsulfate and then concentrated to give2-(2-((5-fluoro-4-(4-fluoro-1sopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetaldehyderepresented by formula I-95-b, which was used in the next step withoutfurther purification.LC-MS: (M+H)⁺=478.

Step 3:

2-(2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetaldehyde(80 mg, 0.167 mmol), sodium acetate (100 mg, 0.73 mmol) andhydroxylamine hydrochloride (70 mg, 1 mmol) were added to 15 mL ethanoland the mixture was stirred at 80° C. for 2 h. The reaction solution wasevaporated to dryness under reduced pressure and then purified by silicagel column chromatography to give2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetaldehyderepresented by formula I-95 (28 mg) as a light yellow solid. ¹H NMR (400MHz, CD₃OD) δ 8.48 (d, J=3.8 Hz, 1H), 8.28 (d, J=0.9 Hz, 1H), 8.22 (d,J=8.5 Hz, 1H), 7.78 (d, J=11.9 Hz, 1H), 7.55-7.42 (m, 1.44H), 6.90 (t,J=4.5 Hz, 0.3H), 4.89-4.83 (m, 1H), 3.71 (d, J=10.8 Hz, 2H), 3.58 (d,J=4.5 Hz, 1H), 3.36 (d, J=6.1 Hz, 2H), 3.06-2.89 (m, 4H), 2.69 (s, 3H),1.74 (t, J=6.5 Hz, 6H). LC-MS: (M+H)⁺=493.

Embodiment 97

Step 1:

Tert-butyl-N-(N-tert-butoxycarbonyl-N′-(trifluoromethylsulfonyl)carbamimidoyl)carbamate(80 mg, 0.21 mmol),6-(2-aminoethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (100 mg, 0.21 mol) and triethylamine (0.5 ml) were addedto 15 mL N,N-dimethylformamide and the mixture was stirred at roomtemperature overnight. The reaction solution was evaporated to drynessunder reduced pressure and then purified by silica gel columnchromatography to givetert-butyl-N-(N-tert-butoxycarbonyl-N′-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methylbenzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)ethyl)carbamimidoyl)carbamicacid represented by the formula I-97-a (130 mg) as a pale yellow solid.LC-MS: (M+H)⁺=721.

Step 2:

Tert-butyl-N-(N-tert-butoxycarbonyl-N′-(2-(2-((5-fluoro-4-(7-fluoro-3-isopropyl-2-methylbenzimidazol-5-yl)pyrimidin-2-yl)amino)-7,8-dihydro-5H-1,6-naphthyridin-6-yl)ethyl)carbamimidoyl)carbamicacid (120 mg, 0.166 mmol) was added to 5 mL dichloromethane and 5 mLtrifluoroacetic acid was added under an ice bath. The mixture wasstirred at room temperature for 3 h, then evaporated to dryness underreduced pressure and purified by preparative HPLC to give2-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)guanidinerepresented by formula I-97 (50 mg) as a light yellow solid. ¹H NMR (400MHz, CD₃OD) δ 8.53 (d, J=3.9 Hz, 1H), 8.32 (d, J=1.2 Hz, 1H), 8.26 (s,1H), 8.16 (d, J=8.5 Hz, 1H), 7.77 (d, J=12.8 Hz, 1H), 7.50 (d, J=8.6 Hz,1H), 4.93 (d, J=6.9 Hz, 1H), 3.73 (s, 2H), 3.48-3.41 (m, 2H), 2.97 (s,4H), 2.84 (t, J=5.7 Hz, 2H), 2.71 (s, 3H), 1.73 (d, J=6.9 Hz, 6H).LC-MS: m/z: (M+H)⁺=521.

Embodiment 107

Triethylamine (0.5 mL) andN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (100 mg, 0.203 mmol) were added to 15 mL drydichloromethane, then dimethylphosphine chloride (30 mg, 0.2667 mmol)was added and the mixture was stirred at room temperature for 3 h. Thereaction solution was evaporated to dryness under reduced pressure andpurified by silica gel column chromatography(DCM/CH₃OH/NH₃.CH₃OH=10/1/0.2) to giveN-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl) -N,P,P-dimethylphosphinic amide represented by formulaI-107 (40 mg) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d,J=3.8 Hz, 1H), 8.22 (dd, J=17.5, 9.9 Hz, 3H), 7.78 (d, J=11.6 Hz, 1H),7.39 (d, J=8.5 Hz, 1H), 4.83-4.67 (m, 1H), 3.77 (s, 2H), 3.29 (dd,J=15.9, 7.0 Hz, 2H), 3.00 (s, 4H), 2.83-2.77 (m, 2H), 2.72 (d, J=11.8Hz, 6H), 1.74 (t, J=9.7 Hz, 6H), 1.50 (d, J=13.2 Hz, 6H). LC-MS: m/z:(M+H)⁺=569.

Embodiment 110

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (100 mg, 0.2 mmol), diisopropylethylamine (0.5 mL) andthiocarbonyldiimidazole(74 mg, 0.41 mmol) were added to 15 mLN,N-dimethylformamide, the mixture was stirred at 50° C. for 3 h. Thereaction solution was cooled to room temperature, 10 mL aqueous ammoniawas added to the above reaction solution, and the mixture was stirredovernight at room temperature. The reaction solution was evaporated todryness under reduced pressure, then purified by silica gel columnchromatography to give1-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-1-methylthiourearepresented by formula I-110 (24 mg) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.68 (d, J=3.9 Hz, 1H), 8.32 (s, 1H), 8.07(d, J=8.5 Hz, 1H), 7.70 (d, J=12.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.25(s, 1H), 4.85 (dt, J=13.9, 7.0 Hz, 1H), 3.64 (s, 2H), 3.11 (d, J=19.9Hz, 2H), 2.86 (d, J=11.9 Hz, 4H), 2.72 (t, J=6.5 Hz, 2H), 2.65 (s, 3H),1.64 (d, J=6.9 Hz, 6H). LC-MS: m/z: (M+H)⁺=552.

Embodiment 132

6-(2-Aminoethyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (120 mg, 0.25 mol) and 1H-pyrazole-1-carboxamidinehydrochloride (73 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide(5 ml), then diisopropylethylamine (350 mg, 2.7 mmol) was added and themixture was stirred at room temperature overnight. The reaction solutionwas evaporated under reduced pressure, and then purified by preparativeHPLC to give1-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)guanidine(28 mg) as a pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=4.0Hz, 1H), 8.38 (s, 2H), 8.29 (d, J=1.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H),7.71 (d, J=12.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 4.93 (d, J=7.0 Hz, 0H),3.69 (s, 0H), 3.45 (t, J=5.6 Hz, 2H), 2.93 (s, 4H), 2.82 (t, J=5.6 Hz,2H), 2.69 (s, 3H), 1.72 (d, J=6.9 Hz, 6H). LC-MS: m/z: (M+H)⁺=521.

Embodiment 133

Step 1:

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (90 mg, 0.15 mmol), tert-butyl (2-oxoethyl)carbamic acid(50 mg, 0.31 mmol) and triethylamine (1 mL) were added to 25 mLdichloromethane, followed by the addition of sodiumtriacetoxyborohydride (65 mg, 0.3 mmol). The mixture was stirred at roomtemperature overnight. The reaction solution was evaporated to drynessunder reduced pressure and the residue was purified by silica gel columnchromatography to give tert-butyl(2-((2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)(methyl)amino)ethyl)carbamaterepresented by formula I-133-a (80 mg) as a pale yellow solid. LC-MS:m/z: (M+H)⁺=636.

Step 2:

Tert-butyl(2-((2-(2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)(methyl)amino)ethyl)carbamate(90 mg, 0.14 mmol) was dissolved in methanol (3 mL), 4 mL solution of 4mol/L hydrochloride in 1,4-dioxane was added, and the resulting solutionwas stirred at room temperature for 2 h. The reaction mixture wasevaporated to dryness under reduced pressure to giveN′-(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-N′-methylethane-1,2-diamine hydrochloride represented byformula I-133-b (80 mg) as a white solid. LC-MS: m/z: (M+H)⁺=536.

Step 3:

N′-(2-(2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-N′-methylethane-1,2-diaminehydrochloride (80 mg, 0.15 mmol) and 1H-pyrazole-1-carboxamidinehydrochloride (45 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide(5 mL) and diisopropylethylamine (350 mg, 2.7 mmol) was added. Themixture was stirred at room temperature overnight, then evaporated todryness under reduced pressure and purified by preparative HPLC to give1-(2-((2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)(methyl)amino)ethyl)guanidine(29 mg) as a pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=3.9Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=1.0 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H),7.78 (d, J=12.0 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 4.93 (d, J=6.9 Hz, 1H),3.97 (s, 2H), 3.37 (t, J=5.7 Hz, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.07 (t,J=5.7 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H), 2.86 (t, J=6.1 Hz, 2H), 2.77 (t,J=5.7 Hz, 2H), 2.71 (s, 3H), 2.42 (s, 3H), 1.73 (d, J=6.9 Hz, 6H).LC-MS: m/z: (M+H)⁺=578.

Embodiment 135

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-aminehydrochloride (100 mg, 0.2 mmol), diisopropylethylamine (0.5 mL) andthiocarbonyldiimidazole (74 mg, 0.41 mmol) were added to 15 mLN,N-dimethylformamide and the mixture was stirred at 50° C. for 3 hours.The reaction mixture was cooled to room temperature and 30 mL methanolwas added. The mixture was stirred overnight at room temperature, thenevaporated to dryness under reduced pressure, and purified by silica gelcolumn chromatography to giveN-(2-(2-((5-fluoro-4-(4-fluoro-1sopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl)-N-methyl-1H-imidazole-1-carbothioamiderepresented by formula I-135 (21 mg) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.71 (d, J=3.9 Hz, 1H), 8.31 (s, 1H),8.16 (d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.70 (d, J=12.2 Hz, 1H), 7.45 (d,J=8.3 Hz, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 5.37 (s, 2H), 4.90-4.76 (m,1H), 3.89-3.75 (m, 2H), 3.55 (d, J=3.7 Hz, 4H), 3.05-2.95 (m, 5H), 2.65(s, 3H), 1.60 (d, J=6.9 Hz, 6H). LC-MS: m/z: (M+H)⁺=603.

Embodiment 137

Step 1:

Diisopropylethylamine (0.5 mL) andN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(132 mg, 0.3 mmol) were added to 15 mL N,N-dimethylformamide,bromoacetonitrile (72 mg, 0.6 mmol) was added and the mixture wasstirred at room temperature for 2 h. The reaction solution wasevaporated to dryness under reduced pressure and then purified by silicagel column chromatography to give2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetonitrilerepresented by formula I-137-a (120 mg) as a pale yellow solid. LC-MS:m/z: (M+H)⁺=475.

Step 2:

2-(2-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetonitrile(120 mg, 0.253 mmol) was added to a mixed solvent of 20 mL ethanol and20 mL tetrahydrofuran, then 0.5 mL 50% aqueous hydroxylamine solutionwas added and the mixture was stirred at 80° C. overnight. The reactionsolution was evaporated to dryness under reduced pressure and thenpurified by silica gel column chromatography to give2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)-N′-hydroxyacetimidamide represented by formula I-137 (85 mg) as a pale yellowsolid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=3.9 Hz, 1H), 8.27 (d, J=0.9Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.75 (d, J=11.5 Hz, 1H), 7.43 (d, J=8.5Hz, 1H), 4.87 (d, J=7.0 Hz, 1H), 3.64 (s, 2H), 3.20 (s, 2H), 2.96 (d,J=5.2 Hz, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.69 (s, 3H), 1.73 (d, J=6.9 Hz,6H). LC-MS: m/z: (M+H)⁺=508.

Embodiment 153

N-(4-(3-Tert-butyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidine-2-yl)-6-(2-chloroethyl)-7,8-dihydro-5H-1,6-naphthyridin-2-amine(50 mg, 0.09766 mmol) (represented by formula 6-b), anhydrousacetonitrile (1 mL) and morpholine (85 mg, 0.9766 mmol) weresuccessively added to a dry flask at room temperature under argonatmosphere. The reaction mixture was stirred at 80° C. for 12 hours.LCMS monitored the reaction was complete. The reaction mixture wascooled to room temperature and concentrated by a rotary evaporator. Theresidue was purified by preparative TLC (silica gel,dichloromethane/methanol=10:1, v/v) to giveN-(4-(3-tert-butyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-6-(2-diethylaminoethyl)-7,8-dihydro-5H-1,6-naphthyridin-2-aminerepresented by formula I-153 (12.8 mg, 0.0227 mmol) as a pale yellowsolid. ¹H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J=3.8 Hz, 1H), 8.38 (d,J=1.2 Hz, 1H), 8.32 (br.s, 1H), 8.24 (d, J=8.5 Hz, 1H), 7.74 (d, J=11.3Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 3.84-3.68 (m, 6H), 3.02-2.93 (m, 4H),2.87 (s, 3H), 2.85-2.79 (m, 2H), 2.75-2.69 (m, 2H), 2.66-2.59 (m, 4H),1.90 (s, 9H). LC-MS m/z: (M+H)⁺=563.40.

Embodiment 155

Step 1:

Vinylmagnesium bromide (25 mL, 0.7 mmol/L) was added to a solution ofmethylphosphonic dichloride (1 g, 7.52 mmol) in tetrahydrofuran at −78°C. in more than half an hour. The mixture was stirred at thistemperature for 3.5 hours, then warmed to 0° C. and stirred for 1 hour.The reaction was quenched with 20 mL saturated ammonium chloridesolution. The mixture was filtered through a pad of silica gel andeluted with 10% 7M methanolic ammonia in dichloromethane. The filtratewas concentrated to give a crude product (0.1 g) as colorless viscousliquid, yield 10%, which was directly used in the next step.

Step 2:

Methyl divinyl phosphine oxide (20 mg, 0.17 mmol) and6-(2-aminoethyl)-N-(4-(1-(tert-butyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(50 mg, 0.1 mmol) were added to a mixed solvent of tetrahydrofuran (6mL) and water (2 mL), then 0.5 mL triethylamine was added and themixture was stirred under reflux overnight. The reaction mixture wasevaporated to dryness under reduced pressure and purified by columnchromatography(methanol:dichloromethane=0-20%) to give a crude product,which was purified by preparative HPLC to give1-(2-(2-((4-(1-(tert-butyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl)-4-methyl-1,4-azaphosphinane4-oxide (8 mg) as a yellow solid, yield 12%. ¹H NMR (400 MHz, CDCl₃) δ8.43 (d, J=8.2 Hz, 2H), 8.26 (d, J=8.1 Hz, 1H), 7.77 (d, J=10.9 Hz, 1H),7.42 (d, J=8.6 Hz, 1H), 3.74 (s, 2H), 2.98 (s, 6H), 2.83 (m, 9H), 1.95(t, 13H), 1.57 (d, J=12.9 Hz, 3H). LC-MS m/z: (M+H)⁺=609.

Embodiment 187

Step 1:

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine(400 mg, 0.918 mmol) and diisopropylethylamine (1 ml) were added to amixed solvent of 10 mL N,N-dimethylformamide and 20 mL acetonitrile,then 2-chloroethyl methyl sulfide (0.6 mL) was added and the mixture wasstirred at 70° C. overnight. Additional 2-chloroethyl methylsulfide (0.6mL) was added and stirred at 70° C. overnight. The mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography to giveN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylthio)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(210 mg) as a yellow solid. LC-MS: m/z: (M+H)⁺=510.

Step 2:

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylthio)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(100 mg, 0.1962 mmol) was added to 10 mL dichloromethane, thenm-chloroperbenzoic acid (42 mg, 0.188 mmol) was added and the mixturestirred overnight at room temperature. The mixture was concentratedunder reduced pressure and purified by silica gel column chromatographyto giveN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylsulfonyl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-aminerepresented by the formula I-187-b (80 mg) as a pale yellow solid.LC-MS: m/z: (M+H)⁺=526.

Step 3:

N-(5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylsulfonyl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine (90mg, 0.17 mmol) and 2-((aminooxy)sulfonyl)-1,3,5-trimethylbenzene (60 mg,0.28 mmol) were added to a mixed solvent of 10 mL dichloromethane and 10mL acetonitrile, the mixture was stirred at room temperature overnight.The solvent was evaporated under reduced pressure and the crude productwas purified by preparative HPLC to giveN-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-benzimidazol-5-yl)pyrimidin-2-yl)-6-(2-(methylsulfonyl)ethyl]-7,8-dihydro-5H-1,6-naphthyridine-2-amine2,4,6-trimethylbenzenesulfonate represented by formula I-187 (30 mg) asa pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J=3.8 Hz, 1H),8.40-8.29 (m, 2H), 7.79 (d, J=11.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 6.88(s, 2H), 4.92 (d, J=6.9 Hz, 2H), 4.78 (s, 1H), 4.07 (s, 4H), 3.76-3.61(m, 1H), 3.52-3.39 (m, 2H), 3.28 (dd, J=14.5, 9.5 Hz, 1H), 2.82 (d,J=3.3 Hz, 3H), 2.71 (s, 3H), 2.63 (s, 6H), 2.24 (s, 3H), 1.73 (d, J=6.9Hz, 6H).LC-MS: (M+H)⁺=541.

Embodiment 197

Diethyl(2-((2-(2-((4-(1-(tert-butyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidin-2(5H)-yl)ethyl)(methyl)amino)ethyl)phosphonate(100 mg, 0.15 mmol) was added to 10 mL dichloromethane, followed by theaddition of trimethylsilyl iodide (0.2 mL). The mixture was stirred atroom temperature overnight. The reaction mixture was evaporated todryness under reduced pressure and the crude product was purified bypreparative HPLC to give(2-((2-(2-((4-(1-(tert-butyl)-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-5-fluoropyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl)(methyl)amino)ethyl)phosphonicacid (50 mg) as a pale yellow solid, yield 54%. ¹H NMR (400 MHz, MeOD) δ8.47 (d, J=3.8 Hz, 1H), 8.41 (d, J=1.1 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H),8.08 (s, 1H), 7.75 (d, J=11.5 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 3.87 (s,2H), 3.24 (m, 4H), 3.13-3.00 (m, 6H), 2.85 (s, 3H), 2.80 (s, 3H),2.04-1.82 (m, 12H). LC-MS: m/z: (M+H)⁺=615.

Embodiment 204

N-(4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)-6-(2-dimethylaminoethyl)-7,8-dihydro-5H-1,6-naphthyridin-2-amine(100 mg, 0.198 mmol) was dissolved in hydrogen peroxide (5 mL), themixture was stirred at room temperature for about 1 hour, then quenchedby adding aqueous sodium sulfite solution. Water was distilled off underreduced pressure. The solid was dissolved in a mixed solvent ofdichloromethane and methanol, then filtered and the filtrate waspurified by HPLC to give2-(2-((4-(3-cyclopropyl-7-fluoro-2-methyl-benzimidazol-5-yl)-5-fluoro-pyrimidin-2-yl)amino)6-oxo-7,8-dihydro-5H-1,6-naphthyridine-6-yl)-N,N-dimethyl-ethylaminooxyrepresented by formula I-205 (30 mg) as a pale yellow solid. ¹H NMR (400MHz, MeOD) δ 8.61-8.47 (br, 2H), 8.02 (s, 1H), 7.52-7.30 (br, 2H),4.60-4.40 (br, 4H), 4.14-3.85 (m, 2H), 3.56-3.70 (br, 4H), 3.48-3.35 (m,2H), 3.02-2.85 (m, 1H), 2.55 (s, 3H), 1.30-1.15 (m, 2H), 1.05-0.84 (m,2H). LC-MS: m/z: (M+H)⁺=537.

Embodiment 205

Diethyl phosphonate (50 mg, 0.36 mmol), triethylamine (0.5 ml) andN-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-6-(2-(methylamino)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-amine(120 mg, 0.24 mmol) were added to a mixed solvent of 10 mL acetonitrile,10 mL carbon tetrachloride and 5 mL dichloromethane, and the mixture wasstirred at room temperature overnight. The reaction mixture was filteredand the filtrate was evaporated to dryness under reduced pressure togive a crude product, which was purified by preparative HPLC to give(2-(2-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethyl)(methyl)phosphoramidate (90 mg) as a pale yellow solid,yield 58%. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=3.8 Hz, 1H), 8.28 (d,J=8.5 Hz, 1H), 8.23 (d, J=1.1 Hz, 1H), 7.80 (d, J=11.7 Hz, 1H), 7.42 (d,J=8.6 Hz, 1H), 4.76 (dd, J=13.9, 6.9 Hz, 1H), 4.10-3.99 (m, 4H), 3.94(dt, J=14.2, 6.8 Hz, 2H), 3.83 (s, 2H), 3.38 (m, 2H), 3.05 (s, 3H), 2.86(t, J=6.9 Hz, 2H), 2.76-2.69 (m, 5H), 1.74 (d, J=7.1 Hz, 6H), 1.37-1.27(t, 6H).

LC-MS m/z: (M+H)⁺=607.

TABLE 1 List of embodiments Embodi- ment Structure Analytic data Method24

White powder. ¹HNMR (400 MHz, DMSO-d₆) δ 10.05 (d, J = 6.7 Hz, 1H), 8.69(s, 1H), 8.31 (s, 1H), 8.14 (t, J = 11.4 Hz, 1H), 7.71 (d, J = 11.9 Hz,1H), 7.65-7.56 (m, 1H), 4.86 (t, J = 5.4 Hz, 1H), 4.68 (d, J = 40.6 Hz,2H), 3.90- 3.80 (m, 2H), 3.62 (d, J = 18.6 Hz, 4H), 3.42 (d, J = 40.8Hz, 4H), 2.88 (d, J = 55.2 Hz, 3H), 2.66 (s, 4H), 1.65 (d, J = 6.9 Hz,7H). LC-MS: m/z: (M + H)⁺ = 563.2. I-5 25

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J = 51.2 Hz, 2H), 8.27(s, 1H), 7.81 (d, J = 12.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 4.80-4.58(m, 1H), 4.42 (s, 1H), 4.15-3.80 (m, 2H), 3.41 (d, J = 25.8 Hz, 2H),3.00 (d, J = 31.7 Hz, 2H), 2.82 (s, 6H), 2.75 (s, 3H), 1.53 (s, 2H),1.33 (d, J = 20.5 Hz, 3H), 1.19 (s, 2H). LC-MS: m/z(M + H)⁺ = 533.2 I-2233

Yellow solid, yield 98% ¹H-NMR (400 MHz, DMSO- d₆) δ 8.78 (d, J = 3.3Hz, 1H), 8.37 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 11.5 Hz,1H), 7.74 (d, J = 8.7 Hz, 1H), 4.50 (s, 1H), 4.28 (s, 2H), 3.50 (t, J =6.1 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 2.79 (s, 3H), 2.22 (d, J = 10.4Hz, 2H), 2.07- 1.95 (m, 2H), 1.86 (d, J = 12.2 Hz, 2H), 1.52 (d, J =22.4 Hz, 1H), 1.27 (d, J = 12.2 Hz, 2H), 0.96 (d, J = 6.4 Hz, 3H).LC-MS: m/z: (M + H)⁺ = 489.9. Preparation embodi- ment 4 34

Yellow solid, yield 94%. ¹H NMR (400 MHz, DMSO- d₆) δ 9.01 (br, 2H),8.70 (d, J = 3.8 Hz, 1H), 8.29 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H),7.78-7.51 (m, 2H), 4.64 (d, J = 32.0 Hz, 2H), 4.39 (s, 1H), 4.17 (d, J =19.2 Hz, 2H), 3.80 (dt, J = 56.6, 5.8 Hz, 2H), 2.91 (d, J = 44.2 Hz,2H), 2.66 (s, 3H), 2.58 (d, J = 3.1 Hz, 3H), 2.24 (d, J = 12.0 Hz, 2H),1.92 (dd, J = 28.7, 12.4 Hz, 3H), 1.52 (s, 1H), 1.34-1.21 (m, 2H), 1.04-0.90 (m, 3H). LC-MS: m/z: (M + H)⁺ = 560.9. I-4 35

Solid. ¹H-NMR (400 MHz, DMSO- d₆) δ = 10.08-10.10 (m, 1H), 8.70 (d, 1H,J = 4 Hz), 8.29 (s, 1H), 8.13-8.17 (m, 1H), 7.68 (d, 1H, J = 12.4 Hz),7.54-7.59 (m, 1H), 4.73 (s, 1H), 4.61 (s, 1H), 4.35-4.38 (m, 1H), 3.79-3.87 (m, 2H), 2.90-2.94 (m, 1H), 2.79-2.82 (m, 1H), 2.66 (s, 4H),2.22-2.29 (m, 8H), 1.86- 1.97 (m, 4H), 1.21-1.29 (m, 3H), 0.95-0.99 (m,3H). LC-MS: m/z: (M + H)⁺ = 575.2. I-5 36

Solid. ¹H-NMR(400 MHz, CDCl₃) δ = 8.44 (d, 1H, J = 3.6 Hz), 8.31 (d, 1H,J = 8.4 Hz), 8.20-8.22 (m, 1H), 7.98-8.03 (m, 1H), 7.76-7.81 (m, 1H),7.46-7.50 (m, 1H), 4.74-4.80 (m, 2H), 4.22-4.29 (m, 1H), 3.92-3.98 (m,2H), 3.29 (s, 2H), 2.94-3.02 (m, 2H), 2.72 (s, 3H), 2.37 (s, 6H),2.22-2.33 (m, 2H), 2.02- 2.08 (m, 4H), 1.86-1.92 (m, 1H), 1.53-1.59 (m,2H). LC-MS: m/z: (M + H)⁺ = 561.2. I-5 38

Solid. ¹H-NMR(400 MHz, DMSO- d₆) δ = 10.12-10.14 (m, 1H), 8.70 (d, 1H, J= 4 Hz), 8.32 (s, 1H), 8.14 (d, 1H, J = 8 Hz), 7.58-7.72 (m, 2H),6.90-6.98 (m, 1H), 6.18 (dd, 1H, J = 16.8 Hz, 2 Hz), 5.75 (dd, 1H, J =10.4 Hz, 2.4 Hz), 4.82-4.88 (m, 1H), 4.68-4.79 (m, 2H), 3.87- 3.92 (m,2H), 2.84-2.92(m, 2H), 2.66(s, 3H), 1.64 (d, 6H, J = 7.2 Hz), 1.24 (s,3H). LC-MS: m/z: (M + H)⁺ = 490.2. I-10 39

Yellow solid 760 mg, yield 98%. ¹H NMR (400 MHz, DMSO- d₆) δ 9.82 (s,2H), 8.83 (d, J = 3.4 Hz, 1H), 8.41 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H),7.92 (d, J = 11.6 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 5.27-5.12 (m, 1H),4.27 (s, 2H), 3.48 (s, 2H), 3.14 (d, J = 5.9 Hz, 2H), 2.93-2.82 (m, 2H),2.76 (s, 3H), 2.71- 2.61 (m, 2H), 2.07-1.89 (m, 3H). LC-MS: m/z: (M +H)⁺ = 447.9. I-28 40

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 10.05 (d, J = 11.9 Hz, 1H), 8.69 (d,J = 3.4 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.81-7.51 (m,2H), 5.00- 4.78 (m, 1H), 4.59 (d, J = 25.3 Hz, 2H), 3.76 (d, J = 39.2Hz, 2H), 3.65-3.46 (m, 2H), 2.83 (d, J = 25.6 Hz, 2H), 2.65 (s, 3H),2.46 (d, J = 8.6 Hz, 2H), 2.25 (dd, J = 22.7, 9.9 Hz, 2H), 1.64 (d, J =6.7 Hz, 6H). LC-MS: m/z: (M + H)⁺ = 532.9. I-4 41

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 10.90 (s, 1H), 9.88 (br, 1H),8.93-8.72 (m, 2H), 8.31 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.83 (d, J =8.8 Hz, 1H), 5.00 (s, 1H), 4.28 (s, 2H), 3.47 (s, 2H), 3.14 (s, 2H),2.79 (s, 3H), 1.68 (d, J = 6.9 Hz, 6H). LC-MS: m/z: (M + H)⁺ = 485.9.I-28 42

Yellow solid 5 mg, yield 11%. ¹H-NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H),8.57 (s, 1H), 8.26-8.15 (m, 2H), 7.55 (s, 1H), 5.14 (s, 2H), 3.99 (d, J= 31.3 Hz, 2H), 3.74 (d, J = 26.0 Hz, 2H), 2.97 (s, 3H), 2.73 (s, 2H),2.64 (s, 3H), 2.44 (s, 2H), 2.21 (d, J = 7.5 Hz, 1H), 2.04 (s, 1H), 1.83(d, J = 6.4 Hz, 6H), 1.61 (s, 1H). LC-MS: m/z: (M + H)⁺ = 547.3. I-4 43

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 3.9 Hz, 1H), 8.44(s, 1H), 8.33-8.20 (m, 2H), 7.84 (d, J = 12.2 Hz, 1H), 7.61 (d, J = 8.8Hz, 1H), 4.61 (s, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.55 (t, J = 5.7 Hz,2H), 3.44- 3.48 (m, 1H), 3.21 (t, J = 5.7 Hz, 2H), 2.95 (t, J = 5.7 Hz,2H), 2.90 (s, 6H), 2.76 (s, 3H), 1.37 (d, J = 5.3 Hz, 2H), 1.20 (s, 2H).LC-MS: m/z: (M + H)⁺ = 548. I-61 44

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 3.9 Hz, 1H), 8.43(s, 1H), 8.33 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 11.9 Hz,1H), 7.58 (d, J = 8.7 Hz, 1H), 5.02-4.88 (m, 1H), 4.60 (s, 2H), 3.79 (t,J = 5.9 Hz, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 6 Hz, 3H), 2.95(t, J = 5.9 Hz, 3H), 2.92 (s, 6H), 2.71 (s, 3H), 1.74 (d,J = 6.9 Hz,6H). LC-MS: m/z: (M + H)⁺ = 550. I-61 45

Pale yellow solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.44 (d, 1H, J = 3.6 Hz),8.19- 8.35 (m, 3H), 7.81(d, 1H, J = 12.0 Hz), 7.46(d, 1H, J = 8.4 Hz),3.95 (s, 2H), 3.32-3.39 (m, 1H), 3.21-3.31 (m, 1H), 3.12 (s, 4H), 2.76(s, 3H), 1.35-1.37 (m, 2H), 1.30(d, 6H, J = 6.4 Hz), 1.13-1.17 (m, 2H).LC-MS m/z: (M + H)⁺ = 476.2 I-3 46

Solid. ¹H-NMR(400 MHz, DMSO- d₆) δ = 9.99 (s, 1H), 8.70 (d, 1H, J = 4Hz), 8.22 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H, J = 8.4 Hz), 4.56 (s, 2H),4.15 (t, 2H, J = 11.6 Hz), 3.71-3.75 (m, 2H), 3.41-3.49 (m, 2H),2.82-2.86 (m, 2H), 2.67 (s, 4H), 2.53-2.56 (m, 3H), 2.22 (s, 6H),1.24-1.28 (m, 3H), 1.12-1.15 (m, 2H). LC-MS: m/z: (M + H)⁺ = 549.2. I-6147

Solid. ¹H-NMR(400 MHz, DMSO- d₆) δ = 9.97 (d, 1H, J = 7.2 Hz), 8.69 (d,1H, J = 4 Hz), 8.21 (s, 1H), 8.10 (d, 1H, J = 8.8 Hz), 7.75 (d, 1H, J =12 Hz), 7.61- 7.66 (m, 1H), 4.56-4.86 (m, 2H), 3.66-3.94 (m, 3H), 3.44-3.48 (m, 1H), 2.79-2.91 (m, 2H), 2.67 (s, 3H), 2.17 (d, 1H, J = 14.4Hz), 1.26-1.30 (m, 2H), 1.13 (s, 2H), 1.05 (d, 3H, J = 6.4 Hz). LC-MS:m/z: (M + H)⁺ = 533.2. I-22 48

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.57 (s, 1H),8.25 (t, J = 8.6 Hz, 2H), 7.57 (d, J = 14.1 Hz, 1H), 5.04-4.94 (m, 2H),4.64 (s, 2H), 4.07 (d, J = 31.7 Hz, 1H), 3.68 (d, J = 47.0 Hz, 2H), 3.04(s, 3H), 2.73 (d, J = 17.8 Hz, 4H), 1.56 (dd, J = 18.3, 6.7 Hz, 7H).LC-MS: m/z: (M + H)⁺ = 519.2. I-22 49

Solid. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 1H), 8.35 (s, 1H), 8.24 (d, J= 8.2 Hz, 1H), 7.81 (d, J = 11.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 5.36(s, 1H), 3.77 (t, J = 5.6 Hz, 2H), 3.64 (t, J = 5.8 Hz, 2H), 3.18-2.88(m, 4H), 2.71 (s, 3H), 2.14 (d, J = 62.1 Hz, 4H), 1.74 (d, J = 6.9 Hz,6H). LC-MS: m/z: (M + H)⁺ = 522.9. I-61 50

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.96 (s, 1H), 8.69 (d, J = 3.9 Hz,1H), 8.22 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 11.7 Hz, 1H),7.57 (d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 5.33 (s, 1H), 4.56 (d, J = 54.3Hz, 4H), 3.67 (t, J = 5.7 Hz, 2H), 3.14 (d, J = 5.8 Hz, 2H), 2.81 (s,2H), 2.67 (s, 3H), 2.14-1.79 (m, 4H). LC-MS: m/z: (M + H)⁺ = 520.9. I-6151

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.07 (s, 2H), 8.88 (t, J = 3.2 Hz,1H), 8.38 (s, 1H), 8.09 (dd, J = 8.8, 3.4 Hz, 1H), 7.94 (dd, J = 45.3,10.2 Hz, 2H), 5.22-5.13 (m, 1H), 4.69 (d, J = 25.5 Hz, 2H), 4.20 (dd, J= 17.8, 12.4 Hz, 2H), 3.83 (dt, J = 52.4, 5.7 Hz, 2H), 3.04 (d, J = 51.3Hz, 2H), 2.82 (dd, J = 20.4, 10.6 Hz, 2H), 2.73 (s, 3H), 2.65 (dd, J =16.9, 7.9 Hz, 2H), 2.58 (d, J = 5.3 Hz, 3H), 1.99 (dd, J = 23.4, 10.6Hz, 2H). LC-MS: m/z: (M + H)⁺ = 518.9. I-4 53

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 10.00 (d, J = 10.1 Hz, 1H), 8.70 (s,1H), 8.18 (d, J = 29.5 Hz, 2H), 7.87-7.57 (m, 2H), 4.67 (d, J = 23.5 Hz,2H), 3.82 (s, 2H), 3.47 (s, 2H), 3.33 (s, 5H), 2.88 (d, J = 49.8 Hz,6H), 2.67 (s, 3H), 1.27 (s, 2H), 1.13 (s, 2H). LC-MS: m/z: (M + H)⁺ =532.9. I-6 54

Solid. ¹H-NMR(400 MHz, DMSO- d₆) δ = 10.02-10.04 (m, 1H), 8.70 (d, 1H, J= 3.6 Hz), 8.35 (s, 1H), 8.11-8.15 (m, 1H), 7.73 (d, 1H, J = 12 Hz),7.58-7.61 (m, 1H), 5.32-5.35 (m, 1H), 5.07-5.12 (m, 1H), 4.61-4.72 (m,2H), 3.80-3.86 (m, 2H), 2.81-2.93 (m, 4H), 2.30 (s, 6H), 1.95-2.04 (m,6H), 1.44-1.48 (m, 2H), 0.84-0.88 (m, 2H). LC-MS: m/z: (M + H)⁺ = 533.2.I-5 55

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 10.06 (d, J = 16.5 Hz, 1H), 8.70 (d,J = 3.8 Hz, 1H), 8.31 (s, 1H), 8.19-8.05 (m, 1H), 7.86-7.52 (m, 2H),4.96- 4.76 (m, 1H), 4.62 (dd, J = 20.8, 13.4 Hz, 2H), 3.77 (d, J = 33.9Hz, 2H), 3.20 (d, J = 9.0 Hz, 2H), 2.84 (d, J = 32.0 Hz, 2H), 2.65 (s,3H), 2.56 (s, 6H), 2.46-2.18 (m, 4H), 1.64 (d, J = 6.8 Hz, 6H). LC-MS:m/z: (M + H)⁺ = 560.9. I-22 57

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (d, J = 3.0 Hz, 1H), 8.58(s, 1H), 8.25 (dd, J = 21.3, 10.1 Hz, 2H), 7.63 (d, J = 9.1 Hz, 1H),4.59-4.46 (m, 4H), 3.75 (t, J = 6.1 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H),3.03 (s, 3H), 1.51- 1.42 (m, 1H), 0.83-0.73 (m, 2H), 0.67 (q, J = 5.1Hz, 2H). LC-MS: m/z: (M + H)⁺ = 448.2. I-28 58

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 8.42 (d, J = 16.9Hz, 1H), 7.93 (d, J = 30.5 Hz, 1H), 7.72 (d, J = 27.6 Hz, 1H), 7.51-7.08(m, 2H), 4.62 (s, 2H), 3.90 (d, J = 32.8 Hz, 1H), 3.77 (d, J = 39.8 Hz,2H), 3.17 (d, J = 22.1 Hz, 2H), 2.91 (d, J = 12.1 Hz, 3H), 2.73 (s, 2H),2.55 (d, J = 36.5 Hz, 3H), 2.16 (d, J = 72.2 Hz, 4H), 1.19 (s, 2H),1.05-0.69 (m, 2H). LC-MS: m/z: (M + H)⁺ = 544.9. I-22 59

Solid. ¹H-NMR(400 MHz, DMSO- d₆) δ9.98-10.00 (m, 1H), 8.69 (d, 1H, J = 4Hz), 8.20-8.21 (m, 2H), 8.12 (d, 1H, J = 8.8 Hz), 7.75 (d, 1H, J = 12.4Hz), 7.62- 7.67 (m, 1H), 4.55-4.82 (m, 2H), 3.80-4.04 (m, 2H), 3.33-3.48 (m, 3H), 3.02-3.06 (m, 1H), 2.80-2.90 (m, 2H), 2.67 (s, 3H),2.28-2.33 (m, 4H), 1.79 (s, 2H), 1.24-1.30 (m, 3H), 1.12- 1.14 (m, 2H).LC-MS: m/z: (M + H)⁺ = 545.2. I-22 60

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, J = 33.2 Hz, 1H), 8.19(d, J = 29.6 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 4.92 (d, J = 13.2 Hz,1H), 4.70 (d, J = 33.6 Hz, 2H), 4.18 (d, J = 41.1 Hz, 4H), 3.88 (d, J =63.1 Hz, 2H), 2.98 (d, J = 36.9 Hz, 2H), 2.85 (s, 6H), 2.71 (s, 3H),0.74- 0.42 (m, 4H). LC-MS: m/z: (M + H)⁺ = 533.2. I-5 63

Solid. ¹H-NMR(DMSO-d₆) δ 9.92 (s, 1H), 8.68 (d, 1H, J = 4 Hz), 8.31 (d,1H, J = 1.2 Hz), 8.06 (d, 1H, J = 8.4 Hz), 7.70 (d, 1H, J = 12 Hz), 7.45(d, 1H, J = 8.4 Hz), 4.82-4.87 (m, 1H), 3.58 (s, 2H), 2.80-2.84 (m, 4H),2.65 (s, 3H), 2.58-2.63 (m, 3H), 2.22 (s, 6H), 1.64 (d, 6H, J = 6.8 Hz).LC-MS: m/z: (M + H)⁺ = 507.9. I-52 64

Pale yellow solid. ¹H-NMR(400 MHz, CD₃OD) δ 8.44-8.45 (m, 1H), 8.35-8.39(m, 1H), 7.93 (s, 1H), 7.59- 7.62(m, 1H), 7.52 (s, 1H), 4.65- 4.74 (m,2H), 3.80-3.98 (m, 4H), 3.37-3.38 (m, 1H), 2.94- 3.03 (m, 2H), 2.75 (s,6H), 2.71 (s, 3H), 1.30-1.34 (m, 2H), 1.15-1.17 (m, 2H). LC-MS: m/z:(M + H)⁺ = 517.2. I-5 65

Solid. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (t, J = 3.2 Hz, 1H), 8.58 (s, 1H),8.25 (dd, J = 12.0, 9.0 Hz, 2H), 7.57 (dd, J = 8.7, 4.8 Hz, 1H), 4.97(dd, J = 17.2, 6.6 Hz, 2H), 4.81 (d, J = 17.6 Hz, 1H), 4.18 (dd, J =108.9, 17.0 Hz, 2H), 3.86 (dd, J = 30.6, 26.8 Hz, 2H), 3.57-3.40 (m,2H), 3.28 (s, 1H), 3.05 (s, 3H), 2.76- 1.90 (m, 4H), 1.67-1.48 (m, 2H),1.35 (d, J = 30.5 Hz, 2H). LC-MS: m/z: (M + H)⁺ = 530.9. I-4 66

White powder. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.57 (s, 1H), 8.25(t, J = 8.6 Hz, 2H), 7.57 (d, J = 14.1 Hz, 1H), 5.04-4.94 (m, 2H), 4.64(s, 2H), 4.07 (d, J = 31.7 Hz, 1H), 3.68 (d, J = 47.0 Hz, 2H), 3.04 (s,3H), 2.73 (d, J = 17.8 Hz, 4H), 1.56 (dd, J = 18.3, 6.7 Hz, 7H). LC-MS:m/z: (M + H)⁺ = 519.2. I-4 67

Solid. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (dd, J = 9.3, 7.7 Hz, 2H), 8.29(d, J = 7.9 Hz, 1H), 7.82 (d, J = 12.3 Hz, 1H), 7.65 (dd, J = 8.7, 4.6Hz, 1H), 4.74 (dd, J = 33.1, 18.6 Hz, 4H), 4.00- 3.82 (m, 2H), 3.51-3.43(m, 2H), 3.04 (d, J = 6.2 Hz, 1H), 2.96 (s, 1H), 2.75 (s, 3H), 2.16-1.91 (m, 4H), 1.41-1.30 (m, 4H). LC-MS: m/z: (M + H)⁺ = 530.9. I-4 68

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.96 (d, J = 2.9 Hz, 1H),8.76 (s, 1H), 8.22 (dd, J = 9.6, 7.2 Hz, 2H), 7.65 (d, J = 8.9 Hz, 1H),4.52 (s, 2H), 3.75 (s, 2H), 3.53 (s, 2H), 3.16 (s, 3H), 2.07 (s, 9H).LC-MS: m/z: (M + H)⁺ = 449.9. I-28 69

Pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.45-8.39 (m, 2H), 8.24 (d,J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 11.5 Hz, 1H), 7.37 (d, J =8.5 Hz, 1H), 3.70 (s, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.94- 2.88 (m, 5H),2.82 (d, J = 6.0 Hz, 2H), 2.77-2.69 (m, 2H), 2.46 (s, 6H), 1.94 (s, 9H).LC-MS: m/z: (M + H)⁺ = 521.0. I-52 70

Yellow powder. ¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J = 3.7 Hz, 1H), 8.23-8.15 (m, 2H), 7.95 (s, 1H), 7.79 (d, J = 11.7 Hz, 1H), 7.39 (d, J = 8.5Hz, 1H), 3.62 (s, 2H), 3.35-3.26 (m, 1H), 2.95 (d, J = 5.8 Hz, 2H), 2.84(t, J = 5.9 Hz, 2H), 2.73 (s, 3H), 2.62 (dd, J = 12.8, 6.0 Hz, 4H), 2.43(s, 6H), 1.91 (dd, J = 14.9, 7.4 Hz, 2H), 1.36-1.31 (m, 2H), 1.14 (d, J= 7.2 Hz, 2H). LC-MS: m/z: (M + H)⁺ = 519.3. I-3 71

Solid. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J = 3.8 Hz, 1H), 8.23 (t, J =5.1 Hz, 2H), 7.99 (s, 1H), 7.80 (d, J = 11.6 Hz, 1H), 7.38 (d, J = 8.5Hz, 1H), 4.75 (dt, J = 14.0, 7.0 Hz, 1H), 3.75 (d, J = 15.3 Hz, 2H),3.53-3.46 (m, 2H), 3.00 (d, J = 5.2 Hz, 2H), 2.96 (d, J = 5.1 Hz, 2H),2.77 (s, 4H), 2.71 (s, 3H), 2.42 (s, 3H), 2.28 (t, J = 2.3 Hz, 1H), 1.73(d, J = 7.0 Hz, 6H). LC-MS: m/z: (M + H)⁺ = 530.9. I-52 74

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 3.9 Hz, 1H), 8.27(s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 12.0 Hz, 1H), 7.54 (d, J= 8.5 Hz, 1H), 3.76 (dd, J = 35.1, 14.8 Hz, 4H), 3.62-3.56 (m, 1H), 3.46(m, 1H), 3.15-3.06 (m, 2H), 3.02- 2.93 (m, 5H), 2.93-2.85 (m, 2H),2.81-2.73 (m, 3H), 2.35 (m, 1H), 2.22-2.00 (m, 2H), 1.88-1.75 (m, 1H),1.37 (m, 2H), 1.22-1.16 (m, 2H). LC-MS m/z: (M + H)⁺ = 530.9. I-3 75

Yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 3.8 Hz, 1H), 8.21(d, J = 8.5 Hz, 2H), 7.89 (s, 1H), 7.78 (d, J = 12.0 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 4.71 (m, 1H), 3.65 (s, 4H), 2.93 (d, J = 3.7 Hz, 2H),2.86 (d, J = 11.6 Hz, 2H), 2.69 (s, 3H), 2.61 (s, 2H), 2.21 (d, J = 12.0Hz, 1H), 2.00 (s, 1H), 1.71 (d, J = 6.9 Hz, 6H), 1.30 (d, J = 11.4 Hz,6H). LC-MS: m/z: (M + H)⁺ = 557.3. I-72 76

Yellow powder. ¹H NMR (400 MHz, DMSO- d₆) δ 9.93 (s, 1H), 8.68 (d, J =3.9 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 12.2Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 4.96-4.78 (m, 1H), 3.65 (d, J = 3.5Hz, 2H), 3.51 (d, J = 2.0 Hz, 2H), 3.23 (s, 1H), 2.85 (dd, J = 10.4, 4.3Hz, 4H), 2.65 (s, 3H), 1.64 (d, J = 6.9 Hz, 6H). LC-MS: m/z: (M + H)⁺ =473.9. I-3 78

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 8.58 (s, 1H), 8.28(s, 1H), 8.15 (s, 1H), 7.51 (s, 1H), 4.10 (s, 2H), 3.64 (dt, J = 9.4,4.4 Hz, 4H), 3.37 (s, 2H), 3.02 (d, J = 24.1 Hz, 4H), 1.50 (d, J = 35.2Hz, 4H), 1.42- 1.27 (m, 6H). LC-MS: m/z: (M + H)⁺ = 504.9. I-77 79

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d, J = 3.9 Hz, 1H), 8.29(s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 11.7 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 4.91 (d, J = 7.1 Hz, 1H), 3.75 (s, 2H), 3.60 (s, 2H),3.40 (s, 2H), 2.97 (s, 4H), 2.69 (s, 3H), 2.38 (s, 6H), 1.72 (d, J = 6.9Hz, 6H). LC-MS: m/z: (M + H)⁺ = 530.9. I-3 81

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.95 (d, J = 3.1 Hz, 1H), 8.55(s, 1H), 8.23 (t, J = 8.1 Hz, 1H), 8.18-8.13 (m, 1H), 7.55 (d, J = 8.9Hz, 1H), 4.29 (s, 2H), 3.90 (s, 1H), 3.72 (s, 2H), 3.51 (s, 4H), 3.02(s, 3H), 1.52 (d, J = 7.2 Hz, 2H), 1.45 (d, J = 6.3 Hz, 2H), 1.35 (s,3H), 1.29 (s, 1H). LC-MS: m/z: (M + H)⁺ = 491.2. I-52 82

Solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.95 (s, 1H), 8.67 (d, J = 3.8 Hz,1H), 8.26 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 12.0 Hz, 1H),7.43 (d, J = 8.4 Hz, 1H), 4.35 (s, 1H), 3.88 (s, 2H), 3.09 (t, J = 5.6Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.64 (s, 4H), 2.20-2.07 (m, 2H),2.06- 1.93 (m, 2H), 0.74 (t, J = 7.3 Hz, 7H). LC-MS: m/z: (M + H)⁺ =464.9. I-39 83

Pale yellow solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.95 (s, 1H), 8.67 (d, J= 3.9 Hz, 1H), 8.26 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 12.4Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 4.39-4.28 (m, 1H), 3.58 (s, 2H), 2.82(dd, J = 9.4, 4.2 Hz, 5H), 2.66-2.57 (m, 7H), 2.22 (s, 7H), 2.13 (dd, J= 16.9, 7.2 Hz, 3H), 2.06-1.95 (m, 3H), 0.74 (t, J = 7.3 Hz, 7H). LC-MS:m/z: (M + H)⁺ = 535.0. I-52 84

White solid. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (d, J = 3.3 Hz, 1H), 8.66(s, 1H), 8.20 (d, J = 11.1 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.79 (d, J= 8.9 Hz, 1H), 4.48 (s, 2H), 4.38-4.25 (m, 1H), 3.71 (dd, J = 10.9, 4.8Hz, 2H), 3.44 (d, J = 6.0 Hz, 2H), 2.95 (s, 3H), 1.84 (t, J = 7.0 Hz,3H), 1.78 (dd, J = 11.8, 5.4 Hz, 1H), 0.93 (m, 1H), 0.82-0.74 (m, 1H),0.69-0.60 (m, 1H), 0.50- 0.38 (m, 1H). LC-MS: m/z: (M + H)⁺ = 462.0.I-28 85

Yellow powder. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 8.43 (s, 1H),8.24 (d, J = 8.5 Hz, 1H), 8.19 (s, 1H), 7.80 (d, J = 11.6 Hz, 1H), 7.41(d, J = 8.5 Hz, 1H), 3.70 (s, 2H), 3.40 (dt, J = 10.5, 8.3 Hz, 2H),2.99-2.95 (m, 4H), 2.76 (s, 3H), 2.69 (s, 6H), 2.60- 2.50 (m, 1H),1.40-1.35 (m, 2H), 1.32 (s, 3H), 1.27 (s, 1H), 1.15 (s, 2H). LC-MS: m/z:(M + H)⁺ = 519.3. I-80 86

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 3.9 Hz, 1H),8.40 (d, J = 1.1 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 11.9Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 4.00 (dq, J = 14.0, 7.0 Hz, 1H), 3.74(s, 2H), 3.03-2.95 (m, 6H), 2.85 (t, J = 6.6 Hz, 2H), 2.67 (s, 3H), 2.62(s, 6H), 1.77 (d, J = 7.0 Hz, 3H), 1.75-1.67 (m, 1H), 0.86 (m, 1H), 0.65(m, 1H), 0.61-0.53 (m, 1H), 0.37- 0.28 (m, 1H). LC-MS: m/z: (M + H)⁺ =533.3. I-52 87

yellow solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.88 (s, 1H), 8.68 (d, J =3.9 Hz, 1H), 8.23 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 12.1Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 3.83 (s, 2H), 3.04 (t, J = 5.8 Hz,2H), 2.73 (t, J = 5.6 Hz, 2H), 2.69 (s, 3H), 1.56 (s, 3H), 1.38-1.13 (m,4H). LC-MS: m/z: (M + H)⁺ = 447.9. I-28 88

Pale yellow solid. ¹H NMR (400 MHz, DMSO- d₆) δ 9.93 (s, 1H), 8.69 (d, J= 3.9 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 12.1Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 3.59 (s, 2H), 2.92- 2.77 (m, 4H),2.69 (s, 3H), 2.61 (dd, J = 15.2, 5.8 Hz, 4H), 2.28 (s, 6H), 1.56 (s,3H), 1.23 (d, J = 11.8 Hz, 4H). LC-MS: m/z: (M + H)⁺ = 518.9. I-52 89

Yellow solid. ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.52 (d, J = 3.8 Hz,1H), 8.31 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 1.1 Hz, 1H), 7.77 (d, J =11.2 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 4.89 (d, J = 6.9 Hz, 1H), 4.25(s, 2H), 3.49 (t, J = 6.0 Hz, 2H), 3.20 (dd, J = 10.9, 5.4 Hz, 4H), 2.70(s, 3H), 1.73 (d, J = 6.9 Hz, 6H), 1.18-1.04 (m, 2H), 0.14 (d, J = 3.3Hz, 9H). LC-MS: m/z: (M + H)⁺ = 536.0. I-3 90

Tawney solid. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J = 3.9 Hz, 1H), 8.51(s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 11.6 Hz, 1H), 7.61 (d, J= 8.4 Hz, 1H), 4.03 (s, 2H), 3.25-3.29 (m, 4H), 3.10-3.12 (m, 2H),3.04-2.97 (m, 2H), 2.95 (s, 6H), 2.89 (s, 3H), 2.23-2.11 (m, 2H), 1.96(s, 9H). LC-MS m/z: (M + H)⁺ = 534.9. I-3 91

Yellow solid. ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.52 (s, 1H), 8.50 (d, J= 3.9 Hz, 1H), 8.28 (d, J = 1.0 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.76(d, J = 11.9 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.90 (d, J = 6.9 Hz,1H), 3.74 (s, 2H), 3.60 (t, J = 5.2 Hz, 2H), 3.10 (s, 3H), 2.97 (s, 4H),2.85 (t, J = 5.3 Hz, 2H), 2.70 (s, 3H), 1.73 (d, J = 6.9 Hz, 6H). LC-MS:m/z: (M + H)⁺ = 535.0. I-72 92

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56-8.52 (m, 1H), 8.51 (s,1H), 8.25 (dd, J = 12.0, 8.6 Hz, 1H), 7.75 (d, J = 11.7 Hz, 1H),7.63-7.54 (m, 1H), 4.72 (d, 10.2 Hz, 2H), 3.95-3.86 (m, 2H), 2.98 m,3H), 2.91-2.80 (m, 6H), 2.52 (d, J = 7.3 Hz, 6H), 1.96 (d, J = 3.3 Hz,9H). LC-MS m/z: (M + H)⁺ = 548.9. 93

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.54 (m, 2H), 8.21 (d, J =8.4 Hz, 1H), 7.79 (d, J = 11.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H),3.98-3.83 (m, 2H), 3.77 (d, J = 1.5 Hz, 2H), 3.70 (td, J = 11.7, 2.2 Hz,2H), 3.04-2.98 (m, 5H), 2.2-2.89 (m, 4H), 2.84-2.71 (m, 2H), 2.66 (dd, J= 13.3, 4.1 Hz, 1H), 2.38 (s, 3H), 2.25 (td, J = 11.8, 3.3 Hz, 1H), 1.97(s, 9H). LC-MS m/z: (M + H)⁺ = 563.3. I-22 94

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 4.0 Hz, 1H),8.51 (d, J = 1.1 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 11.7Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 4.01 (dd, J = 12.5, 2.7 Hz, 1H),3.96-3.90 (m, 1H), 3.86 (s, 2H), 3.75 (td, J = 11.9, 2.2 Hz, 1H),3.10-3.07 (m, 3H), 3.04- 3.0 (m, 3H), 2.95 (d, J = 12.7 Hz, 1H), 2.89(s, 3H), 2.87- 2.82 (m, 1H), 2.79-2.76 (m, 1H), 2.54-2.35 (m, 4H), 1.96(s, 9H). LC-MS m/z: (M + H)⁺ = 563.3. I-22 96

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J = 3.8 Hz, 1H),8.27 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.81-7.74 (m, 1H),7.45 (d, J = 8.6 Hz, 1H), 4.85 (p, J = 6.9 Hz, 1H), 3.69 (s, 2H), 3.42(t, J = 7.2 Hz, 2H), 2.98-2.89 (m, 4H), 2.83 (s, 3H), 2.73-2.68 (m, 2H),2.68 (s, 3H), 2.04 (s, 3H), 1.73 (s, 3H), 1.71 (s, 3H). LC-MS m/z: (M +H)⁺ = 550.3. I-95 98

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.52 (d, J = 3.9 Hz, 1H),8.19 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 12.0 Hz, 1H), 7.48(d, J = 8.5 Hz, 1H), 5.05 (dd, J = 17.6, 8.8 Hz, 1H), 3.70 (s, 2H), 2.95(dd, J = 10.0, 4.4 Hz, 4H), 2.78 (s, 4H), 2.70 (s, 3H), 2.44 (s, 6H),2.31-2.22 (m, 4H), 2.08 (td, J = 12.9, 6.7 Hz, 2H), 1.90 (dt, J = 9.6,3.4 Hz, 2H). LC-MS m/z: (M + H)⁺ = 533.3. I-52 101

White solid. 1H NMR (400 MHz, CD₃OD) δ 8.98 (d, J = 3.2 Hz, 1H), 8.76(s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 10.8 Hz, 1H), 7.65 (d, J= 9.1 Hz, 1H), 4.84- 4.79 (m, 1H), 3.83 (dt, J = 11.0, 5.7 Hz, 1H),3.74-3.66 (m, 1H), 3.62-3.49 (m, 2H), 3.17 (s, 3H), 2.07 (s, 9H), 1.81(d, J = 6.8 Hz, 3H). LC-MS m/z: (M + H)⁺ = 464.3. I-28

102

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.52 (d, J = 4.0 Hz, 1H), 8.32(s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 12.1 Hz, 1H), 7.44 (d, J= 8.2 Hz, 1H), 4.42 (t, J = 12.6 Hz, 1H), 3.66 (s, 2H), 2.92 (dd, J =13.7, 4.3 Hz, 4H), 2.78-2.68 (m, 7H), 2.40 (s, 6H), 2.31-2.22 (m, 2H),2.02 (d, J = 11.2 Hz, 4H), 1.84 (d, J = 14.7 Hz, 1H), 1.67-1.57 (m, 2H),1.42-1.27 (m, 2H). LC-MS m/z: (M + H)⁺ = 547.3. I-52 103

White solid. 1H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 3.9 Hz, 1H), 8.51(s, 1H), 8.39 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 11.6 Hz,1H), 7.57 (d, J = 8.6 Hz, 1H), 4.04 (q, J = 6.6 Hz, 1H), 3.39-3.35 (m,1H), 3.30-3.23 (m, 1H), 3.12-2.95 (m, 5H), 2.93 (s, 6H), 2.89 (s, 3H),2.84- 2.76 (m, 1H), 1.96 (s, 9H), 1.43 (d, J = 6.7 Hz, 3H). LC-MS m/z:(M + H)⁺ = 535.3. I-52

104

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.98 (d, J = 3.2 Hz, 1H), 8.76(s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.24 (d, J = 10.8 Hz, 1H), 7.65 (d, J= 9.1 Hz, 1H), 4.84- 4.79 (m, 1H), 3.83 (dt, J = 11.0, 5.7 Hz, 1H),3.74-3.66 (m, 1H), 3.62-3.49 (m, 2H), 3.17 (s, 3H), 2.07 (s, 9H), 1.81(d, J = 6.8 Hz, 3H). LC-MS m/z: (M + H)⁺ = 464.3. I-28

106

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 4.0 Hz, 1H), 8.51(d, J = 1.1 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 11.5 Hz,1H), 7.57 (d, J = 8.6 Hz, 1H), 4.02 (q, J = 6.6 Hz, 1H), 3.29-3.22 (m,1H), 3.17 (dd, J = 9.6, 5.9 Hz, 2H), 3.00 (m, 4H), 2.89 (s, 3H),2.85-2.81 (m, 1H), 2.78 (s, 6H), 1.96 (s, 9H), 1.42 (d, J = 6.7 Hz, 3H).LC-MS m/z: (M + H)⁺ = 535.3. I-52

108

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 3.8 Hz, 1H), 8.36(s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 11.6 Hz, 1H), 7.50 (d, J= 8.2 Hz, 1H), 4.43 (t, J = 13.2 Hz, 1H), 3.74 (s, 2H), 3.03-2.95 (m,6H), 2.86 (t, J = 6.5 Hz, 2H), 2.71 (s, 3H), 2.63 (s, 6H), 2.38 (dd, J =24.7, 10.6 Hz, 2H), 2.09-1.94 (m, 4H), 1.67-1.50 (m, 1H), 1.44- 1.27 (m,2H), 1.05 (d, J = 6.4 Hz, 3H). LC-MS m/z: (M + H)⁺ = 561.3. I-52 109

White solid. 1H NMR (400 MHz, CD₃OD) δ 8.96 (s, 1H), 8.76 (s, 1H), 8.23(d, J = 10.1 Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 4.94 (s, 1H), 4.64-4.48(m, 2H), 3.93 (s, 1H), 3.62-3.59 (m, 1H), 3.16 (s, 3H), 2.07 (s, 9H),1.63 (d, J = 2.1 Hz, 3H). LC-MS m/z: (M + H)⁺ = 464.3. I-28

111

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.97 (d, J = 3.2 Hz, 1H), 8.77(s, 1H), 8.26 (s, 1H), 8.23 (d, J = 2.9 Hz, 1H), 7.62 (d, J = 9.0 Hz,1H), 4.63-4.50 (m, 2H), 3.99-3.88 (m, 1H), 3.64-3.60 (m, 1H), 3.41-3.35(m, 1H), 3.17 (s, 3H), 2.07 (s, 9H), 1.64 (d, J = 6.4 Hz, 3H). LC-MSm/z: (M + H)⁺ = 464.2. I-28

112

White solid. 1H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 3.9 Hz, 1H), 8.52(d, J = 1.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.80 (d, J= 12.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 3.88 (s, 2H), 3.41-3.37 (m,2H), 3.28 (dd, J = 8.2, 4.8 Hz, 1H), 3.01- 2.97 (m, 2H), 2.91 (m, 10H),2.69 (dd, J = 17.2, 4.9 Hz, 1H), 1.97 (s, 9H), 1.21 (d, J = 6.6 Hz, 3H).LC-MS m/z: (M + H)⁺ = 535.3. I-52

114

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 4.0 Hz, 1H), 8.52(d, J = 1.1 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 11.6 Hz,1H), 7.56 (d, J = 8.5 Hz, 1H), 3.89 (s, 2H), 3.42-3.35 (m, 3H), 3.17(dd, J = 17.2, 5.3 Hz, 1H), 3.00 (td, J = 5.2, 1.4 Hz, 2H), 2.93 (s,6H), 2.90 (s, 3H), 2.69 (dd, J = 17.2, 4.7 Hz, 1H), 1.97 (s, 9H), 1.21(d, J = 6.6 Hz, 3H). LC-MS m/z: (M + H)⁺ = 535.3. I-52

126

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.15 (d, J = 7.7Hz, 2H), 7.80 (d, J = 12.3 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 4.23 (d, J= 6.8 Hz, 2H), 3.70 (s, 2H), 2.94 (d, J = 9.3 Hz, 4H), 2.79 (s, 3H),2.69 (s, 4H), 2.47 (s, 6H), 0.89 (t, J = 7.4 Hz, 1H), 0.66 (d, J = 3.0Hz, 2H), 0.51 (d, J = 10.7 Hz, 2H). LC-MS: m/z: (M + H)⁺ = 519.3. I-52127

Yellow powder. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J = 51.2 Hz, 2H), 8.27(s, 1H), 7.81 (d, J = 12.6 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 4.80-4.58(m, 1H), 4.42 (s, 1H), 4.15-3.80 (m, 2H), 3.41 (d, J = 25.8 Hz, 2H),3.00 (d, J = 31.7 Hz, 2H), 2.82 (s, 6H), 2.75 (s, 3H), 1.53 (s, 2H),1.33 (d, J = 20.5 Hz, 3H), 1.19 (s, 2H). LC-MS: m/z(M + H)⁺ = 533.2.I-22 129

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56-8.47 (m, 2H), 8.17 (d, J =8.5 Hz, 1H), 7.75 (d, J = 11.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 3.94(d, J = 13.4 Hz, 1H), 3.84 (m, 1H), 3.76-3.63 (m, 3H), 3.07-2.85 (m,10H), 2.65 (m, 3H), 1.95 (s, 9H). LC-MS m/z: (M + H)⁺ = 549.3. I-77 130

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.56-8.47 (m, 2H), 8.17 (d, J =8.5 Hz, 1H), 7.75 (d, J = 11.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 3.94(d, J = 13.4 Hz, 1H), 3.84 (m, 1H), 3.76-3.63 (m, 3H), 3.07-2.85 (m,10H), 2.65 (m, 3H), 1.95 (s, 9H). LC-MS m/z: (M + H)⁺ = 549.3. I-77 131

Yellow solid. 1H NMR (400 MHz, CDCl₃) δ 8.40 (d, J = 3.7 Hz, 1H), 8.26-8.10 (m, 2H), 7.99 (s, 1H), 7.78 (d, J = 11.9 Hz, 1H), 7.38 (d, J = 8.4Hz, 1H), 3.69 (q, J = 14.6 Hz, 2H), 3.61-3.52 (m, 1H), 3.30 (t, J = 5.3Hz, 1H), 3.12 (dd, J = 13.2, 7.4 Hz, 1H), 2.94 (s, 3H), 2.86 (d, J = 5.7Hz, 1H), 2.74 (d, J = 4.0 Hz, 5H), 2.62 (ddd, J = 33.3, 13.4, 7.3 Hz,2H), 1.97-1.76 (m, 3H), 1.39-1.29 (m, 3H), 1.25 (s, 2H), 1.13 (t, J =8.0 Hz, 2H). LC-MS: m/z: (M + H)⁺ = 531.3. I-3 134

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 3.9 Hz, 1H),8.49 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 11.8Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 4.94 (s, 1H), 3.76 (s, 2H), 3.38 (d,J = 5.5 Hz, 2H), 3.30- 3.23 (m, 2H), 3.02-2.93 (m, 6H), 2.90 (s, 3H),2.71 (s, 3H), 1.74 (d, J = 6.9 Hz, 6H), 1.11- 0.99 (m, 2H), 0.11 (s,9H). LC-MS m/z: (M + H)⁺ = 593. I-3 136

Pale yellow solid. 1H NMR (400 MHz, D₂O) δ 8.34 (s, 1H), 7.81 (d, J =3.8 Hz, 1H), 7.12 (s, 2H), 6.90 (s, 1H), 6.77 (d, J = 12.1 Hz, 1H), 4.82(s, 3H), 4.12 (s, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.85 (s, 2H), 2.20 (s,3H). LC-MS m/z: (M + H)⁺ = 408.2. I-21 138

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.49 (d, J = 3.8 Hz, 1H), 8.10(d, J = 7.1 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 11.6 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 2H), 3.01 (t, J = 6.3 Hz, 2H),2.94 (s, 4H), 2.85 (t, J = 6.5 Hz, 2H), 2.64 (s, 9H). LC-MS m/z: (M +H)⁺ = 479.3. I-52 139

Yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.97 (d, J = 3.3 Hz, 1H), 8.56(s, 1H), 8.23 (dd, J = 16.0, 10.1 Hz, 2H), 7.63 (d, J = 9.0 Hz, 1H),4.67 (q, J = 7.3 Hz, 2H), 4.52 (s, 2H), 3.75 (t, J = 6.3 Hz, 2H), 3.53(t, J = 6.1 Hz, 2H), 3.00 (s, 3H), 1.61 (t, J = 7.3 Hz, 3H). LC-MS m/z:(M + H)⁺ = 422.2. I-21 140

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.52 (d, J = 3.9 Hz, 1H),8.13 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H), 7.78 (d, J = 12.0 Hz, 1H), 7.51(d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.77 (s, 2H), 3.44-3.39(m, 2H), 2.97 (m, 12H), 2.69 (s, 3H), 1.48 (t, J = 7.3 Hz, 3H). LC-MSm/z: (M + H)⁺ = 493.3. I-52 141

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 573.2. I-52 142

Pale yellow solid. 1H NMR (400 MHz, DMSO- d₆) δ 9.91 (s, 1H), 8.68 (d, J= 3.9 Hz, 1H), 8.22 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 12.5Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.52 (d, J = 40.3 Hz, 4H), 3.33 (s,17H), 2.75 (dt, J = 70.0, 16.4 Hz, 14H), 2.59- 2.35 (m, 20H), 2.35 (s,1H), 2.32 (s, 3H), 1.28 (s, 2H), 1.20 (d, J = 53.8 Hz, 3H). LC-MS m/z:(M + H)⁺ = 491.2. I-77 143

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 575.2. I-52 145

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 440.2. Preparation embodi- ment4 146

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 511.3. I-52 147

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 458.2. Preparation embodi- ment4 148

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 529.3. I-52 149

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 476.2. Preparation embodi- ment4 150

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 547.2. I-52 151

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 490.3. Preparation embodi- ment4 152

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 561.3. I-52 154

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 4.0 Hz, 1H),8.48 (d, J = 1.0 Hz, 1H), 8.43 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.73(d, J = 11.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 3.93 (s, 2H), 3.15 (dd,J = 17.9, 12.0 Hz, 6H), 3.07-2.97 (m, 5H), 2.94-2.84 (m, 8H), 2.72 (s,3H), 1.95 (s, 9H). LC-MS m/z: (M + H)⁺ = 576.3. I-52 156

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 490.3. I-52 157

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J = 4.0 Hz, 1H),8.48 (d, J = 1.2 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 11.5Hz, 1H), 7.47 (dd, J = 8.5, 4.5 Hz, 1H), 3.84 (t, J = 5.3 Hz, 2H), 3.79(s, 1H), 3.71 (dd, J = 10.1, 5.3 Hz, 1H), 3.35 (s, 2H), 3.19-3.14 (m,2H), 3.04- 2.92 (m, 6H), 2.86 (s, 3H), 2.82 (s, 3H), 1.93 (s, 9H).LC-MS: m/z: (M + H)⁺ = 551.30. I-72 158

Pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 3.8 Hz, 1H),8.39 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.73(d, J = 11.4 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 3.66 (s, 2H), 2.95 (t, J= 6.0 Hz, 2H), 2.89 (d, J = 5.6 Hz, 2H), 2.86 (s, 3H), 2.77-2.67 (m,6H), 2.67- 2.61 (m, 2H), 2.40 (s, 6H), 2.36 (s, 3H), 1.90 (s, 9H). LC-MSm/z: (M + H)⁺ = 578.40. I-153 159

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 611.2. I-3 160

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J = 4.0 Hz, 1H),8.48 (d, J = 1.0 Hz, 1H), 8.43 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.73(d, J = 11.7 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 3.74 (s, 2H), 3.39 (t, J= 5.6 Hz, 2H), 3.31-3.23 (m, 2H), 2.96 (m, 6H), 2.91 (s, 3H), 2.88 (s,3H), 1.95 (s, 9H), 1.10-1.02 (m, 2H), 0.11 (s, 9H). LC-MS m/z: (M + H)⁺= 607.3. I-72 161

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 627.2. I-52 162

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 591.3. I-52 163

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 462.3. Preparation embodi-ment4 164

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 533.3. I-52 165

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 464.2. Preparation embodi-ment4 166

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 535.2. I-52 167

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 466.2. Preparation embodi-ment4 168

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 537.2. I-52 169

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 484.2. Preparation embodi-ment4 170

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 555.2. I-52 171

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 450.2. Preparation embodi-ment4 172

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 521.2. I-52 173

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 463.2. Preparation embodi-ment4 174

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 534.2. I-52 175

Yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J = 3.9 Hz, 1H), 8.31(d, J = 1.3 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 12.0 Hz,1H), 7.46 (d, J = 8.6 Hz, 1H), 4.94-4.87 (m, 1H), 3.66 (s, 2H), 3.44 (t,J = 6.7 Hz, 2H), 2.93 (d, J = 4.9 Hz, 2H), 2.90 (d, J = 5.0 Hz, 2H),2.70 (d, J = 6.6 Hz, 2H), 2.68 (s, 3H), 1.95 (s, 3H), 1.72 (s, 3H), 1.70(s, 3H). LC-MS m/z: (M + H)⁺ = 520.3. I-3 176

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J = 4.2 Hz, 1H),8.36 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 11.5 Hz, 1H),7.29-7.21 (m, 1H), 3.52 (s, 2H), 2.80 (d, J = 12.8 Hz, 9H), 2.66 (d, J =6.6 Hz, 2H), 2.44 (s, 3H), 1.87 (s, 9H). LC-MS m/z: (M + H)⁺ = 507.3.I-77 177

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 590.3. I-95 178

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 547.3. I-72 179

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 545.3. I-72 180

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 579.3. I-52 181

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 611.2. I-187 182

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 609.3. I-187 183

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 610.3. I-187 185

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 598.3. I-187 186

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 612.3. I-187 188

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 545.3. I-52 189

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 549.3. I-52 190

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 535.3. I-52 191

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 535.3. I-52 192

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 549.3. I-52 193

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 563.3. I-52 194

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 563.3. I-52 195

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 643.3. I-3 196

Pale yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 8.46 (br.s, 1H), 8.41 (d, J= 3.9 Hz, 1H), 8.35 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.70(d, J = 11.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 4.19 (pd, J = 7.2, 3.4Hz, 4H), 3.65 (s, 2H), 3.24 (q, J = 7.6 Hz, 1H), 3.17- 3.11 (m, 1H),3.07 (q, J = 7.3 Hz, 1H), 3.01 (dd, J = 11.0, 8.3 Hz, 1H), 2.97-2.86 (m,6H), 2.84 (s, 3H), 2.79 (t, J = 6.6 Hz, 2H), 2.66 (q, J = 8.2 Hz, 1H),2.51-2.39 (m, 1H), 2.09-1.99. (m, 1H), 1.88 (s, 9H), 1.32 (t, J = 7.1Hz, 6H). I-153 LC-MS m/z: (M + H)⁺ = 699.35. 198

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (d, J = 4.3 Hz, 1H),8.40 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 11.7 Hz, 1H), 7.28(d, J = 8.5 Hz, 1H), 4.21- 4.05 (m, 4H), 3.54 (s, 2H), 2.90- 2.73 (m,9H), 2.66 (s, 4H), 2.33 (s, 3H), 2.13-2.02 (m, 2H), 1.90 (s, 9H), 1.34(t, J = 7.1 Hz, 6H). LC-MS m/z: (M + H)⁺ = 671.3. I-72 199

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 522.3. I-137 200

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 550.3. I-137 202

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.50-8.40 (m, 3H), 8.22 (d,J = 8.3 Hz, 1H), 7.75 (d, J = 11.6 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H),3.71 (s, 2H), 3.14 (t, J = 5.6 Hz, 2H), 3.01-2.91 (m, 4H), 2.86 (d, J =6.7 Hz, 5H), 1.94 (s, 9H). LC-MS m/z: (M + H)⁺ = 536. I-71 203

Pale yellow solid. 1H NMR (400 MHz, CD₃OD) δ 8.50 (d, J = 4.2 Hz, 1H),8.13 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 12.0 Hz, 1H), 7.28(d, J = 8.4 Hz, 1H), 3.54 (s, 2H), 2.81 (dd, J = 16.5, 5.2 Hz, 6H),2.72-2.64 (m, 5H), 2.45 (s, 3H), 1.57 (s, 3H), 1.25 (t, J = 6.3 Hz, 2H),1.20 (t, J = 5.6 Hz, 2H). LC-MS m/z: (M + H)⁺ = 505. I-71 206

Pale yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J = 4.5 Hz, 1H),8.24 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 11.6 Hz, 1H), 7.04(d, J = 8.3 Hz, 1H), 3.52- 3.34 (m, 3H), 2.79 (s, 3H), 2.74- 2.61 (m,11H), 2.46-2.39 (m, 1H), 1.81 (s, 9H), 1.21 (d, J = 6.5 Hz, 3H). LC-MSm/z: (M + H)⁺ = 535.40. I-3 207

1H-NMR(400 MHz, CD₃OD) δ = 8.53 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 0.8Hz, 1H), 8.41 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 12.0 Hz,1H), 7.50 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 3.83 (s, 2H), 3.78 (s, 2H),3.40-3.32 (m, 4H), 3.02- 3.00 (m, 6H), 2.89 (s, 3H), 2.47- 2.53 (m, 2H),1.96 (s, 9H). LC-MS: m/z: (M + H)+ = 603.4. I-153 208

Pale yellow solid. 1H NMR (400 MHz, DMSO- d6) δ9.95 (s, 1H), 8.68 (s,1H), 8.46 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 11.4 Hz, 1H),7.46 (d, J = 8.0 Hz, 1H), 3.64 (s, 2H), 3.39 (s, 3H), 3.03 (s, 3H), 2.84(d, J = 6.7 Hz, 8H), 1.88 (s, 9H). LC-MS m/z: (M + H)+ = 556.2. I-3 209

Pale yellow solid. 1H NMR (500 MHz, DMSO- d6) δ10.80 (s, 1H), 9.98 (d, J= 4.9 Hz, 1H), 8.67 (d, J = 3.8 Hz, 1H), 8.45 (s, 1H), 8.13-7.97 (m,1H), 7.67 (d, J = 11.6 Hz, 1H), 7.52-7.35 (m, 2H), 3.58 (d, J = 15.6 Hz,2H), 3.41 (d, J = 4.2 Hz, 1H), 3.24 (d, J = 6.1 Hz, 1H), 2.87-2.77 (m,7H), 1.86 (s, 9H). LC-MS: 507.2(M + H)⁺. I-95 210

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 521.2. I-77 211

Pale yellow solid. LC-MS m/z: (M + H)⁺ = 605.2. I-207

Effect Embodiment 1

Test method:

CDK kinase inhibitory activity assay used LANCE® Ultra technique, testcompounds were screened on CDK4/CycD3, CDK6/CycD3 and CDK2/CycA2 kinasesat ATP concentration of Km. During the test, the initial concentrationof the test compound was 3333 nM, each test compound set 10 seriallydiluted concentrations, the dilution fold was 3-fold, each concentrationset 2 duplicated wells.

CDK4/CycD3, CDK6/CycD3 and CDK2/CycA2 were purchased from CarnaBiosciences, Inc.; dimethyl sulfoxide, ATP, DTT solution were purchasedfrom Sigma-Aldrich; EDTA solution was purchased from GIBCO; LANCE®Detection Buffer, 10× and LANCE® UltraEuropium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) and LANCE®Ultra ULight™-eIF4E-binding protein 1 (Thr37/46) Peptide were purchasedfrom Perkinelmer.

Test Procedure:

1. Take 10 mM stock solution of the test compound, in 96-well compoundplate, DMSO was used to dilute the compound to an initial concentrationof 100×, then this concentration was used as the first concentration,3-fold diluted to make 10 serial concentrations; 1 μL each serialdilution was then added to 19 μL 1× reaction buffer to prepare 5×compound for use; 2 μL 5× compound was transferred from 96-well plate to384-well plate; compound-free control well was added with 2 μL thefollowing liquid: 1× reaction buffer with the addition of 1 μL DMSO; 2μL 250 mM EDTA was added to the Min control well.

2.1 × reaction buffer was used to formulate the kinase, substrate andATP into a 2.5× enzyme/substrate mixture and 2.5× ATP solutionrespectively. In the experiment, the final concentration of CDK4/CycD3kinase is 0.76 ng/μL, the final concentration of ATP is 80 μM; the finalconcentration of CDK6/CycD3 kinase is 0.5 ng/μL, the final concentrationof ATP is 50 μM; the final concentration of CDK2/CycA2 kinase is 0.86ng/μL, the final concentration of ATP is 15 μM; the final concentrationof CDK2/CycE1 kinase is 1.016 ng/μL, the final concentration of ATP is20 μM; 2.5× enzyme/substrate mixture was added to a 384-well plate,incubated at room temperature for 5 minutes; then added with 2.5× ATPsolution, reacted at room temperature for 30 minutes.

3. LANCE® Detection Buffer was used, 1× to prepare 2× LANCE® UltraEuropium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) for use. Afterthe enzymatic reaction was continued for 30 minutes, 10 mM EDTA wasadded to 384-well plate and the mixture was reacted at room temperaturefor 5 minutes. Then LANCE® Ultra Europium-anti-phospho-eIF4E-bindingprotein 1 (Thr37/46) was added, reacted at room temperature for 1 hour.

4. The 384-well plate was placed in HERAEUS Multifuge X1R centrifuge,centrifuged at 2000 rpm for 2 minutes; data were measured on EnVision™,337 nM wavelength laser was used as the excitation light, test at RFU665nM and RFU615 nM, and RFU665 nM/RFU615 nM×10000 was used as the finaldata for analysis.

5. Graphpad Prism 5.0 was used to perform Log (inhibitor) vs.response-Variable slope (four parameters) curve fitting on the data andthe corresponding IC₅₀ (half maximal inhibitory concentration) wascalculated.

The test result was shown in Table 3.

TABLE 2 Structures of comparative examples A-F and LY2835219 comparativeexample A

comparative example B

comparative example C

comparative example D

comparative example E

comparative example F

LY2835219

TABLE 3 Activity test results on Kinase level Compound CDK4 CDK6 CDK2number IC₅₀, nM IC₅₀, nM IC₅₀, nM LY2835219 2.51 11.7 52.2 I-3 2.08 10.435.0 I-4 1.72 3.49 29.6 I-5 1.64 4.14 33.7 I-6 1.72 7.57 28.7 I-8 2.057.07 15.5 I-9 1.74 7.09 13.4 I-10 2.21 7.81 10.4 I-12 3.55 14.2 60.4I-13 42.3 327 558 I-14 14 140 1090 I-15 20.1 113 306 I-17 2.54 4.88 37.2I-19 2.34 12.4 38.2 I-20 4.49 22.3 7.34 I-21 4.84 25.0 128 I-22 3.4910.6 193 I-23 2.88 4.17 14.8 I-24 3.90 6.44 31.1 I-25 3.08 5.78 57.9I-26 2.23 8.12 37.2 I-27 5.23 14.1 151 I-28 4.11 18.9 143 I-29 1.81 4.98304 I-30 2.23 3.38 154 I-31 2.35 4.84 20.4 I-32 3.54 13.2 146 I-33 1.656.23 65.5 I-34 2.07 2.56 89.7 I-35 1.97 4.53 87.6 I-36 2.75 7.41 281I-37 4.68 16.1 413 I-38 2.34 4.37 32.3 I-39 2.18 7.43 72.1 I-40 2.533.59 40.6 I-41 74.9 272 >3330 I-42 7.05 13.4 84.3 I-43 2.94 3.57 122I-44 3.21 2.82 54.1 I-45 7.14 22.7 710 I-46 2.52 3.42 346 I-47 2.36 4.16559 I-48 1.65 4.88 91.0 I-49 3.36 5.17 28.2 I-50 2.71 3.94 334 I-51 1.832.88 129 I-52 3.88 3.81 700 I-53 1.70 5.46 314 I-54 4.27 7.50 294 I-552.47 3.56 58.9 I-57 3.55 6.14 109 I-58 3.20 6.14 93.7 I-59 3.14 4.7893.4 I-60 1.47 3.47 79.4 I-61 1.12 2.55 364 I-62 1.44 4.51 28.3 I-631.12 2.0 47.7 I-64 3.26 8.47 >1020 I-65 1.35 3.75 >3470 I-66 1.06 6.36661 I-67 1.53 6.24 212 I-68 1.09 2.97 18.5 I-69 1.13 1.57 54.9 I-70 1.685.51 1490 I-71 1.34 3.47 167 I-72 1.12 2.58 110 I-73 3.14 6.91 371 I-742.08 3.15 317 I-75 3.37 5.16 74.9 I-76 2.45 4.58 33.9 I-77 2.07 3.15 249I-78 4.41 5.60 567 I-79 1.92 2.69 35.5 I-80 2.22 3.67 647 I-81 1.68 3.34207 I-82 0.86 3.16 16.5 I-83 1.08 1.55 17.4 I-84 1.54 3.21 15.0 I-850.94 2.54 135 I-86 0.96 1.49 16.3 I-87 0.92 2.21 10.3 I-88 0.91 1.4116.3 I-89 3.74 17.9 62.4 I-90 1.16 1.56 28.5 I-91 0.99 1.70 16.3 I-920.99 1.39 14.3 I-93 0.96 1.33 16.3 I-94 1.16 1.37 10.3 I-95 1.18 2.026.02 I-97 1.73 2.11 15.0 I-98 1.04 5.01 670 I-101 1.79 2.90 14.5 I-1021.02 2.41 19.2 I-103 1.02 0.97 23.8 I-104 4.21 9.25 31.1 I-106 1.33 2.6783.3 I-107 1.56 4.59 135 I-108 1.61 2.23 116 I-109 1.59 3.86 30.7 I-1102.00 5.89 14.5 I-111 1.09 2.98 11.2 I-112 1.37 1.70 44.9 I-114 1.74 1.7723.6 I-126 2.21 6.26 232 I-127 1.65 4.88 444 I-129 0.70 1.13 62.4 I-1301.02 1.48 14.3 I-131 0.91 1.41 28.5 I-132 0.99 0.77 19.4 I-133 1.52 1.8278.2 I-134 1.35 1.59 25.1 I-135 17.7 111 147 I-136 14.1 84.2 486 I-1371.55 4.78 8.43 I-138 4.26 33.0 >3330 I-139 8.12 29.3 126 I-140 2.35 5.67358 I-142 1.96 3.25 301 I-153 2.26 1.87 42.8 I-154 1.9 1.97 39.6 I-1551.45 2.08 67.0 I-157 2.06 2.03 48.4 I-158 1.27 1.60 73.1 I-160 3.77 2.4634.6 I-175 1.86 3.86 21.0 I-176 1.49 1.51 6.68 I-192 1.54 1.53 29.0I-196 3.06 2.99 60.2 I-197 15.9 12.9 27.6 I-198 1.91 2.03 59.3 I-1991.53 2.31 27.0 I-200 2.15 5.89 40.2 I-202 1.14 1.11 20.8 I-203 1.51 1.2820.0 I-204 12.1 25.7 1250 I-205 4.83 14.7 117 I-206 1.56 1.76 50.3 I-2072.27 1.73 32.0 I-208 1.39 2.58 13.1 I-209 1.48 2.39 14.0 I-210 2.11 1.8018.0 I-211 1.45 1.36 18.5 comparative 3.80 13.2 17.0 example Acomparative 2.93 7.58 13.5 example B comparative 2.37 7.26 21.5 exampleC comparative 2.06 7.22 31.9 example D comparative 2.06 9.17 19.9example E comparative 1.72 2.67 22.5 example F

Effect Embodiment 2

MCF-7, T-47D, ZR-75-1, COLO 205 and A549 cell proliferation inhibitionassays were performed using the CellTiter-Glo® Luminescent CellViability Assay method. Experiments were performed on human breastcancer MCF-7, T-47D and ZR-75-1 cell, human colon cancer COLO 205 cell,and human non-small cell carcinoma A549 cell, used CellTiter method todetermine the inhibition effect of the compound on proliferation of fivecell lines. During the test, the initial concentration of the testcompound was 10 μM, all test compounds set 10 serially dilutedconcentrations, the dilution-fold was 3-fold, each concentration set 2duplicated wells.

Mcf-7 cell, purchased from ATCC, article No. HTB-22;

T-47D, purchased from ATCC, article No. HTB-133;

ZR-75-1, purchased from Shanghai Cell Bank,article No. TCHu126;

COLO 205 human colon cancer cell, purchased from Cell Bank of TypeCulture Collection of the Chinese Academy of Sciences/Cell BankShanghaiInstitutes for Biological Sciences, Chinese Academy of Sciences,catalogue No. TCHu102;

A549 human non-small cell cancer cell, purchased from ATCC, catalogueNo. CCL-185™;

CellTiter-Glo® luminescent cell viability assay kit, purchased fromPromega, Catalog No. G7573;

RPMI-1640, purchased from Life technologies, article No. A1049101;

F-12K Nutrient Mixture, purchased from Life technologies, article No.21127-002;

FBS, purchased from Life technologies, article No. 10099-141;

Antibiotic, purchased from Life technologies, article No. 10378-016;

PBS, purchased from Life technologies, article No. 10010-023;

Dimethyl sulfoxide, purchased from Sigma-Aldrich, article No. D8418;

384-well cell culture plate, purchased from Corning, article No. 3570.

Test Procedure:

1. Normally cultured human breast cancer cells, normally cultured 12thgeneration COLO 205 human colon cancer cells, and normally cultured 7thgeneration A549 cells were plated in 384-well plate at a certain celldensity; MCF-7 and T-47D cells were plated at a density of 500cells/well, ZR-75-1, COLO 205 cells and A549 cells were plated at adensity of 250 cells/well, the cell culture plate was placed at 37° C.in 5% CO₂ condition for 24 hours.

2. One day after human breast cancer cells were plated, one plate wasused to measure the background Celltiter value which was recorded asControl D1. Dosing on the remaining plates to set cell control group.The initial concentration of the test compound was 10 μM, followed by 10serial dilutions, the dilution-fold was 3-fold, each concentration set 2duplicated well.

2′. After COLO 205 cells and A549 cells were plated for 24 hours, theconfigured concentration gradient of drug was added to the correspondingcell wells, respectively. The control group Conctrol was a drug-free,medium solution containing 0.2% DMSO. The untreated cell well was usedto measure the background value which was recorded as Blank. The cellculture plate was placed at 37° C., COLO 205 cells were cultured in 5%CO₂ condition for 6 days, A549 cells were cultured in 5% CO₂ conditionfor 4 days.

3. Human breast cancer cells: After 6 days treatment of the testcompound, 50 μL CellTiter detection solution was added to each well, themixture was shaken for 2 min, mixed thoroughly, centrifuged, left tostand for 10 min, the fluorescent signal was recorded. The drug groupwas recorded as Drug D7. The control group was recorded as Control D7.

3′. COLO 205 cells and A549 cells: the microplate was taken out fromincubator and equilibrated at room temperature for 30 minutes. 50 μLCellTiter-Glo® Luminescent Cell Viability Assay which had beenequilibrated at room temperature was added to each well, the mixture wasshaken at 700 rpm at room temperature for 2 minutes, the microplate wasplaced in HERAEUS Multifuge X1R centrifuge at 2000 rpm for 1 minute;equilibrated at room temperature for 10 minutes, the fluorescence signalvalue was measured on EnVision™.

4. Graphpad Prism 5.0 was used to perform Log (inhibitor) vs.response-Variable slope (four parameters) curve fitting on the data andthe corresponding IC₅₀ (half maximal inhibitory concentration)wascalculated.

The test results were shown in Table 4, wherein the structures ofcomparative examples A-F refer to those recited in effect embodiment 1.

TABLE 4 Activity results at Cell level COLO MCF-7 T-47D ZR-75-1 205 A549Compound IC₅₀, IC₅₀, IC₅₀, IC₅₀, IC₅₀, number nM nM nM nM nM LY2835219116. 38.4 108 411 436 I-3 82.1 79.3 110 213 I-4 185 267 85.2 103 I-569.4 9.02 78.4 121 I-6 119 322 253 I-8 154 110 63.2 267 I-9 241 418 176I-10 895 8680 838 I-12 138 141 1390 I-13 3520 2880 4940 I-14 1590 13702230 I-15 >33300 >33300 4760 I-17 176 330 314 I-19 533 198 426 I-20 2090985 3390 I-21 684 809 335 I-22 245 116 324 I-23 108 20.7 187 120 I-2493.5 464 235 I-25 96.3 39.4 139 235 I-26 145 637 301 I-27 275 122 1260I-28 525 212 381 I-29 28.0 16.9 50.0 352 I-30 188 229 1010 I-31 218 660369 I-32 457 4930 605 I-33 648 1320 269 I-34 116 131 141 I-35 92.3 66.073.9 1150 I-36 140 32.9 72.5 542 I-37 666 243 409 1150 I-38 94.1 137 219161 I-39 2490 137 146 816 I-40 1090 484 369 303 I-41 1320 1430 1500 786I-42 1050 1200 354 575 I-43 1590 26.1 60.5 598 I-44 771 410 126 367 I-452810 283 352 1340 I-46 15.8 47.0 160 522 I-47 35.0 58.8 62.1 637 I-4827.9 32.5 119 1210 I-49 1590 396 220 195 I-50 88.0 34.6 68.8 614 I-51314 42.0 83.4 461 I-52 23.3 19.8 25.5 563 49.3 I-53 73.2 23.4 57.0 468317 I-54 94.1 30.3 56.2 573 I-55 377 16.4 82.5 360 I-57 214 1120 210 478I-58 431 56.0 88.9 485 I-59 62.3 44.0 35.8 533 I-60 36.2 24.3 61.4 521I-61 41.5 13.1 68.6 361 I-62 22.6 21.9 49.9 194 I-63 7.03 8.62 21.5 94.575.3 I-64 443 72.7 244 3600 I-65 139 33.0 109 72.9 I-66 165 48.1 1421340 I-67 182 43.8 74.3 607 465 I-68 73.8 131 75.3 96.1 I-69 18.7 5.0514.1 56.0 58.7 I-70 102 56.7 139 1420 125 I-71 609 2000 692 871 I-72 247797 130 219 I-73 344 21.3 184 1270 I-74 21.0 8.05 36.1 302 44.1 I-75 30864.6 272 463 I-76 461 197 232 375 I-77 163 26.9 61.4 541 I-78 136 87.9164 803 I-79 39.4 14.8 53.6 202 I-80 32.7 42.0 69.6 431 30.8 I-81 14529.9 60.0 449 I-82 27.4 130 65.7 150 I-83 12.6 8.26 13.6 68.0 179 I-8422.2 73.9 52.0 93.2 I-85 69.1 16.3 174 250 69.0 I-86 19.9 7.81 29.3 84.093.1 I-87 98.4 189 97.0 130 72.6 I-88 21.0 6.29 16.8 70.8 93.3 I-89 522738 492 770 573 I-90 27.9 8.99 14.5 105 140 I-91 1940 336 1300 3530 3130I-92 115 18.5 80.0 78.3 69.9 I-93 44.6 14.0 141 189 441 I-94 48.9 25.1114 335 376 I-95 56.4 179 85.7 114 226 I-97 1380 375 1610 2690 6830 I-9849.3 47.7 191 578 612 I-101 31.0 61.9 50.7 89.8 54.4 I-102 54.0 62.8 1411130 1510 I-103 6.99 5.21 16.3 50.4 139 I-104 71.6 237 162 199 148 I-10623.4 34.7 123 170 337 I-107 551 29.0 110 387 934 I-108 239 118 674 17302190 I-109 28.1 94.3 76.7 157 74.7 I-110 152 344 353 350 451 I-111 19.477.9 46.4 89.4 70.0 I-112 21.1 4.69 15.0 44.2 195 I-114 7.73 3.24 9.6540.7 259 I-126 21.2 26.2 61.8 284 68.5 I-127 27.9 32.5 118 1210 I-12933.1 9.18 133 299 353 I-130 47.14 9.04 45.10 572.50 454 I-131 44.5 30.577.2 762 1360 I-132 39.6 405 731 >10000 >10000 I-133 882 810 1360 62102690 I-134 86.2 750 479 189 352 I-135 963 1680 1260 1310 1290 I-136 10801670 1420 1870 1550 I-137 185.90 140.40 268.40 386.20 482 I-138 224 188608 2290 3570 I-139 756 808 452 929 1180 I-140 23.2 15.2 80.5 384 2900I-142 224 15.0 57.9 265 816 I-153 14.8 333.6 41.5 80.6 169 I-154 72.99.89 31.3 68.3 I-155 157 106 40.2 425 I-157 296 7.20 19.4 42.2 113 I-15876.0 45.0 82.5 546 I-160 118 70.5 438 240 424 I-175 612 74.4 261 117 305I-176 238 5.91 40.4 11.4 37.2 I-187 454 340 574 660 1100 I-192 17.4 10.617.7 I-196 51.7 1500 149 425 I-197 957 1240 >10000 7620 >10000 I-19895.6 26.6 114 96.0 213 I-199 135 169 92.0 I-200 399 76.6 132 125 422I-202 158 36.0 122 59.4 52.0 I-203 29.8 4.25 14.9 26.1 205 I-204 568 5551930 5830 >10000 I-205 150 140 452 1060 I-206 20.5 17.8 35.2 I-207 67.2484 74.8 I-208 66.8 182 56.0 I-209 86.2 127 76.5 I-210 54.6 28.2 72.8I-211 88.7 229 56.1 comparative 79.1 129 108 114 example A comparative134 229 309 114 example B comparative 148 119 75.1 371 example Ccomparative 152 406 367 example D comparative 176 134 59.3 132 example Ecomparative 291 740 178 example F

Effect Embodiment 3

In vitro proliferation inhibition experiments of U87, MGU251, K562,THP1, HepG2, SK-HEP-1, SNU-5, N87, H1975, H1993, CFPAC_(1,) PANC-1,LNCap, and PC-3 cell lines was used CellTiter-Glo® luminescent cellviability assay method. Experiments were performed on U87, MGU251, K562,THP1, HepG2, SK-HEP-1, SNU-5, N87, H1975, H1993, CFPAC_(1,) PANC-1,LNCap and PC-3 cells, CellTiter method was used to determine theinhibition effect of the compound on proliferation. During the test, theinitial concentration of the test compound was 10 μM, each test compoundset 10 serially diluted concentrations, the dilution-fold was 3-fold,each concentration set 2 duplicated wells.

U87MG human brain astrocytoma cell line, purchased from ATCC, articleNo. HTB-14

K-562 cell, purchased from Cell Bank of Type Culture Collection of theChinese Academy of Sciences, article No. TCHu191;

PANC-1 cell, purchased from Cell Bank of Type Culture Collection of theChinese Academy of Sciences, article No. TCHu98;

THP1 cell, purchased from ATCC, article No. TIB-202;

HepG2 human hepatoma cell line, purchased from ATCC, article No.HB-8065;

SK-HEP-1 cell, purchased from Cell Bank of Type Culture Collection ofthe Chinese Academy of Sciences, article No. TCHu109;

SNU-5 cell, purchased from ATCC, article No. CRL-5973;

N87 cell, purchased from ATCC, article No. CRL-5822;

H1975 non-small cell lung cancer cell, purchased from ATCC, article No.CRL-5908;

H1993 cell, purchased from ATCC, article No. CRL-5909;

CFPAC1 cell, purchased from ATCC, article No. CRL-1918;

MGU251 cell, purchased from Cell Bank of Type Culture Collection of theChinese Academy of Sciences, article No. TCHu58;

LNCap cell, purchased from ATCC, article No. CRL-1740;

PC-3 cell, purchased from ATCC, article No. TCHu158;

RPMI-1640 medium, purchased from Life technologies, article No.A1049101;

IMDM medium, purchased from Life technologies, article No. 12440;

DMEM medium, purchased from Life technologies, article No. 11995;

MEM medium, purchased from Life technologies, article No. 51200;

FBS, purchased from Life technologies, article No. 10099;

Antibiotic, purchased from Life technologies, article No. 10378;

PBS, purchased from Life technologies, article No. 10010;

β-mercaptoethanol, purchased from Life technologies, article No.1150809;

F-12K, purchased from Life technologies, article No. 21127022;

HepG2, purchased from ATCC, article No. HB-8065; U87MG, purchased fromATCC, article No. HTB-14; PC-3, purchased from Cell Bank, Shanghai,article No. TCHu158; CellTiter-Glo® luminescent cell viability assaykit, purchased from Promega, Catalog No. G7573; 384-well cell cultureplate, purchased from Corning, article No. 3570; 96-well compound plate,purchased from Nunc, article No. 267245.

Test Procedure:

1. U87MG (DMED medium, 11th generation, 12th generation and 13thgeneration), MGU251 (4th generation), K562 (10th generation, cell platedensity 125 cells/well), THP1 (6th generation, 8th generation and 10thgeneration), HepG2 (DMED medium, 7th generation, 10th generation and13th generation), SK-HEP-1 (7th generation), SNU-5 (5th generation), N87(1640 medium, Assay1: 11th generation, Assay2: 12th generation, Assay3:13th generation), H1975 (RPMI medium, 6th generation, 9th generation,11th generation), H1993 (8th generation), CFPAC₁ (IMDM medium, Assay1:9th generation, Assay2: 10th generation, Assay3: 12th generation),PANC-1 (5th generation), LNCap (7th generation, 10th generation and 12thgeneration, cell plate density 625cells/well), PC-3 (8th generation),plated in 384-well plate at a cell density of 250 cells/well.

2. One day after plated, one plate was used to measure the backgroundCelltiter value which was recorded as Control D1. Dosing on theremaining plates to set cell control group. The initial concentration ofthe test compound was 10 μM, followed by 10 serial dilutions, thedilution-fold was 3-fold, each concentration set 2 duplicated well.

3. After certain days (U87MG cell for 4 days, MGU251 cell for 6 days,K562 cell for 4 days, THP1 cell for 4 days, HepG2 cell for 4 days,SK-HEP-1 cell for 4 days, SNU-5 cell for 6 days, N87 cell for 4 days,H1975 cell for 4 days , H1993 cell for 6 days, CFPAC1 cell for 4 days,PANC-1 cell for 4 days, LNCap cell for 6 days, PC-3 cell for 6 days) oftreatment of the test compound, 50 μL CellTiter detection solution wasadded to each well, the mixture was shaken for 2 min, mixed thoroughly,centrifuged, left to stand for 10 min, detected and recorded thefluorescent signal. The drug group was recorded as Drug D7. The controlgroup was recorded as Control D7.

4. Graphpad Prism 5.0 was used to perform Log (inhibitor) vs.response-Variable slope (four parameters) curve fitting on the data andthe corresponding IC₅₀ (half maximal inhibitory concentration) wascalculated.

The test results were shown in Table 5 and Table 6.

TABLE 5 Activity data of I-52 on different tumor cells Cell LY283521(IC₅₀, nM) I-52 (IC₅₀, nM) line Assay1 Assay2 Assay3 Assay1 Assay2Assay3 HepG2 246 204 198 35.5 22.6 21.8 U87MG 711 792 614 37.9 35.5 22.2LNCap 73.2 81.0 97.8 35.6 67.0 37.5 PC-3 5850 11800 >10000 4190 876037500 THP1 251 123 187 36.8 34.1 36.6

TABLE 6 Activity data of I-63 on different tumor cells Cell LY283521(IC₅₀, nM) I-63 (IC₅₀, nM) line Assay1 Assay2 Assay3 Assay1 Assay2Assay3 U87 711 792 614 198 154 267 MGU251 232 403 246 111 181 114 K562974 1110 1190 211 334 352 THP1 251 123 187 61.5 40.9 44.8 HepG2 246 204198 33.3 24.7 21.8 SK-HEP-1 430 401 402 147 108 153 SNU-5 422 460 685226 206 340 N87 573 592 391 392 530 346 H1975 603 1040 677 346 367 268H1993 1120 1240 1100 1000 619 663 CFPAC1 508 378 228 2670 178 272 PANC-1664 658 782 288 373 297 LNCap 73.2 80.9 97. 8 16.1 31.7 20.1 PC-3 585011800 8310 541 535 1480

Effect embodiment 4 (in vivo pharmacodynamics of the compounds on humanbreast cancer MCF-7 cell in BALB/c nude mice subcutaneous xenograftmodel)

Experimental Objective:

Evaluate in vivo pharmacodynamics of the test compounds on human breastcancer MCF-7 cell in BALB/c nude mice subcutaneous xenograft model.

Experimental Design:

64 of BALB/c nude mices, 6-8 weeks old, weight 18-22 g, female, providedby ShanghaiSippr-bk Laboratory Animal Ltd., according to Table 7.

TABLE 7 In vivo pharmacodynamics of experimental animals grouping anddosage regimen Dosing Administration Dosing Group N¹ compound Dosevolume route frequency 1 8 menstruum — 10 mL/kg PO QD × 19 days 2 8 Testcompound  25 10 mL/kg PO QD × 19 I-52 mg/kg days 3 8 Test compound  5010 mL/kg PO QD × 19 I-52 mg/kg days 4 8 Test compound 100 10 mL/kg PO QD× 19 I-52 mg/kg days 5 8 Test compound  10 10 mL/kg PO QD × 19 I-63mg/kg days 6 8 Test compound  25 10 mL/kg PO QD × 19 I-63 mg/kg days 7 8Test compound  50 10 mL/kg PO QD × 19 I-63 mg/kg days 8 8 Test compound50 10 mL/kg PO QD × 19 LY2835219 mg/kg days Note: N¹: the number of miceper group Dosing volume: 10 μL/g based on the weight of mice. If theweight loss exceeded 15%, the dosage regimen should be adjustedaccordingly.

Experiment Route:

1. Cell culture: human breast cancer cell line MCF-7 was cultured in amonolayer in vitro, the culture condition was in accordance with thesupplier's technical specification or the references. Passage cells weretreated with trypsin-EDTA for conventional digestion twice a week. Whenthe cell saturation was 80%-90% and the quantity reached therequirements, cells were collected, counted, and inoculated.

2. Estrogen tablet inoculation and urination: 2 days before cellinoculation, the β-estradiol sustained-release tablet was inoculatedinto the left back of each mice. One week after inoculation, the animalurinated 3 times per week, the animal urinated daily if necessary.

3. Tumor cell inoculation: 0.2 mL 10×10⁶ MCF-7 cells was subcutaneouslyinoculated into the right back of each nude mice (PBS: Matrigel=1:1).When the average tumor volume reached 195 mm³, the compound wasadministered according to the dosage regimen(see Table 7).

4. Preparation of the test sample, see Table 8.

TABLE 8 Preparation method of the test compounds Concen- StorageCompound Preparation method tration condition vehicle 1, liquid A:Taking 16.6 m/L 1% 4° C., in phosphoric acid, adding water dark to 1000mL, shaking; 2, liquid B: Taking 7.163 g disodium phosphate, addingwater to 100 mL and making it dissolved; 3, mixing 145 mL the liquid Aand 55 mL liquid B, shaking; adding 350 mL pure water, mixing, shaking,determining pH with pH meter to give the phosphate buffer (20 mM, pH2.0); 4, weighing 5 g hydroxyethyl cellulose, taking 500 mL phosphatebuffer (20 mM, pH 2.0), mixing under magnetic stirring, storing at 4° C.in dark ready for use. I-52 Weighing 18 mg compound 2.5 mg/mL 4° C., inI-52, being added to 7.2 mL dark 1% HEC in phosphate buffer, mixinguntil homogeneous I-52 Weighing 36 mg compound 5 mg/mL 4° C., in I-52,being added into 7.2 mL dark 1% HEC in phosphate buffer, mixing untilhomogeneous I-52 Weighing 72 mg compound 10 mg/mL 4° C., in I-52, beingadded into 7.2 mL dark 1% HEC in phosphate buffer, mixing untilhomogeneous I-63 Weighing 7.2 mg compound 1 mg/mL 4° C., in I-52, beingadded into 7.2 mL dark 1% HEC in phosphate buffer, mixing untilhomogeneous I-63 Weighing 18 mg compound 2.5 mg/mL 4° C., in I-52, beingadded into 7.2 mL dark 1% HEC in phosphate buffer, mixing untilhomogeneous I-63 Weighing 36 mg compound 5 mg/mL 4° C., in I-52, beingadded into 7.2 mL dark 1% HEC in phosphate buffer, mixing untilhomogeneous LY2835219 Weighing 36 mg compound 5 mg/mL 4° C., inLY2835219, being added into dark 7.2 mL 1% HEC in phosphate buffer,mixing until homo- geneous Note: It is necessary to gently homogeneouslymix the drug before the drug was administered to the animal.

5. Tumor measurement and experimental indicator: The experimentalindicator was to examine whether the tumor growth was inhibit, delayedor cured. Tumor diameter was measured twice a week with a verniercaliper. The formula for calculating the tumor volume was V=0.5a×b², aand b denoted the long diameter and short diameter of the tumorrespectively. The antitumor activity of the compounds was evaluated byTGI(%) or relative tumor proliferation rate T/C(%). TGI(%) reflected thetumor growth inhibition rate. Calculation for TGI(%): TGI (%)=[(1−(meantumor volume at the end of dosing of a treatment group−mean tumor volumeat the beginning of dosing of the treatment group))/(mean tumor volumeat the end of treatment of the solvent control group-mean tumor volumeat the beginning of treatment of the solvent control group)]×100%.Relative tumor proliferation rate T/C(%): the calculation formula was asfollows: T/C%=T_(RTV)/C_(RTV)×100% (T_(RTV): RTV of treatment group;C_(RTV): RTV of solvent control group). The relative tumor volume (RTV)was calculated based on the result of tumor measurement, the calculationformula was RTV=V_(t)/V₀, wherein V₀ was the mean tumor volume measuredat the beginning (d₀) of dosing, and Vt was the mean tumor volumemeasured at a certain time, T_(RTV) and C_(RTV) took at the same day. Atthe end of the experiment, the tumor weight was measured and the tumorweight inhibition rate IR(%) was calculated: the calculation formula wasIR(%)=(1−Tw/Vw)×100, Tw: mean tumor weight of the treatment group, Vw:mean tumor weight of the solvent control group.

6. Data summary and statistical analysis: The treatment group showed thebest treatment effect on the 19th day after dosing at the end of theexperiment. Therefore, based on the data, statistical analysis wasperformed to evaluate the differences between groups. T-test was usedfor the comparison between two groups, and one-way ANOVA was used forcomparison among three groups or multiple groups. If the variance wasnot homogeneous, the Games-Howell method was used for test. If variancewas homogeneous, the Dunnet (2-sided) method was used for analysis. Alldata analysis were performed with SPSS 19.0.p<0.05 was consideredstatistically significant.

Experimental Results

1. Comparison between two groups of the treatment group relative to thecontrol group, see Table 9.

TABLE 9 pharmacodynamics of the compound of the inhibition on MCF-8xenograft tumorgrowth Day 6 Day 13 Day 19 T/C^(a) TGI^(a) T-test T/C TGIT-test T/C TGI T-test Group (%) (%) p^(b) (%) (%) p (%) (%) p Vehicle —— — — — — — — — LY283 68.96 111.13 0.044 46.02 94.99 0.023 36.58 82.660.032 5219  50 mg/ kg I-52 69.27 110.04 0.047 38.21 108.73 0.013 33.6686.41 0.028  25 mg/ kg I-52 66.78 118.92 0.040 35.49 113.46 0.011 23.09100.18 0.016  50 mg/ kg I-52 63.65 130.17 0.028 29.9 123.36 0.007 19.44104.95 0.013 100 mg/ kg I-63 66.45 120.15 0.036 45.53 95.84 0.022 39.4978.82 0.038  10 mg/ kg I-63 68.73 111.98 0.047 31.43 120.67 0.008 19.49104.88 0.014  25 mg/ kg I-63 34.11 235.8 0.001 14.48 150.43 0.003 9.82117.45 0.009  50 mg/ kg Note: ^(a)tumor growth inhibition was calculatedby T/C and TGI (TGI(%) = [1-(T_(6/13/19)-T₀)/(V_(6/13/19)-V₀)] × 100);^(b)p-value comparedthe treatment group with the vehicle group usingT-test according to tumor volume.

Each treatment group exhibited inhibitory activity on tumor growth atthe 6th day, 13th day and 19th day after dosing compared to the controlgroup. At 19th day after dosing, the mean tumor volume of tumor-bearingmice in the solvent control group reached 840 mm³, compared to that, theeffect of the test compounds I-52, I-63 and LY2835219 at different doseswas statistically significant. The tumor growth inhibition rate (TGI) ofcompound I-52 at 25, 50 and 100 mg/kg reached 86.41%, 100.18%, and104.95%, respectively; the tumor weight inhibition rate (IR) was 72.92%,81.93%, and 86.35%, respectively; The tumor growth inhibition rate (TGI)of compound I-63 at 10, 25 and 50 and mg/kg reached 78.82%, 104.88%, and117.45%, respectively; the tumor weight inhibition rate (IR) was 60.42%,83.38%, and 92.26%, respectively; the tumor growth inhibition rate (TGI)of LY2835219 at 50 mg/kg reached 82.66%, the tumor weight inhibitionrate (IR) was 56.18%. The T-test indicated that there was astatistically significant difference with between the treatment groupand the vehicle group (p<0.05).

2. Comparison between compound 1-52 and compound 1-63 at 50 mg/kg, seeTable 10.

TABLE 10 Comparison of antitumor activity at 50 mg/kg on MCF-7 xenografttumor model(based on the tumor volume on the 19th day after dosing)Tumor volumn (mm³)^(a) T/C^(b) TGI^(b) Group (19th day) (%) (%) Pvalue pvalue LY2835219 306 ± 30 36.58 82.66 0.008^(d) — 50 mg/kg I-52 193 ± 2623.09 100.18 — 0.008^(e) 50 mg/kg I-63 82 ± 7 9.82 117.45 0.015^(d)0.000^(e) 50 mg/kg Note: ^(a)mean value ± SEM; ^(b)tumor growthinhibition was calculated by T/C and TGI (TGI(%) = [1 − (T₁₉ − T₀)/V₁₉ −V₀)] × 100); c. p-value was calculated based on tumor volume;^(d)compared to I-52, 50 mg/kggroup; ^(e)compared to LY2835219, 50mg/kggroup.

The one-way ANOVA or T-test analysis of the two compounds at 50 mg/kgindicated that there was a significant difference in the inhibitoryeffect of the three compounds at the same dose on this model (p<0.05)(Table 10)

3. Dose-effect analysis of compound I-52 and I-63, see Table 11

TABLE 11 Comparison of anti-tumor activity of compound I-52 and I-63 atdifferent dose on MCF-7 xenograft tumor model (based on the tumor volumeon the 19th day after dosing) Tumor volumn (mm³)^(a) T/C^(b) TGI^(b)Group (19th day) (%) (%) P value P value I-52 283 ± 23 33.66 86.41 —0.004^(e) 25 mg/kg I-52 193 ± 26 23.09 100.18 0.031^(d) 0.570^(e) 50mg/kg I-52 163 ± 22 19.44 104.95 0.004^(d) — 100 mg/kg I-63 332 ± 3239.49 78.82 — 0.000^(g) 10 mg/kg I-63 164 ± 16 19.49 104.88 0.002^(f )0.003^(g) 25 mg/kg I-63 82 ± 7 9.82 117.45 0.000^(f ) — 50 mg/kg Note:^(a)mean value ± SEM; ^(b)tumor growth inhibition was calculated by T/Cand TGI (TGI(%) = [1 − (T₁₉ − T₀)/(V₁₉ − V₀)] × 100); c. p-value wascalculated based on tumor volume; ^(d)compared to I-52, 25 mg/kg group;^(e)compared to I-52, 100 mg/kg group; ^(f)compared to I-63, 10 mg/kggroup; ^(g)compared to I-63, 50 mg/kg group;

When one-way ANOVA analysis was performed on the three dose groups ofcompound I-52 respectively, the result indicated that at differentdoses, there was a significant difference in the anti-tumor activitybetween the low dose group of compound I-52 and the middle, high dosegroup of compound I-52 (p<0.05), but there was no significant differencebetween the medium dose group and the high dose group (Table 10).

When one-way ANOVA analysis was performed on the three dose groups ofcompound I-63 respectively, the result indicated that at differentdoses, there was a significant difference in the anti-tumor activity ofcompound I-63 (Table 11).

Effect Embodiment 5

Test Method:

CDK kinase inhibitory activity assay used LANCE® Ultra technique, testcompounds were screened on CDK1/CycB, CDKS/p25, CDK7/CycH/MAT1 andCDK9/CycT1 kinases at ATP concentration of Km. During the test, theinitial concentration of the test compound was 3333 nM, each testcompound set 10 serially diluted concentrations, the dilution-fold was3-fold, each concentration set 2 duplicated wells.

CDK1/CycB, CDKS/p25 and CDK7/CycH/MAT1 were purchased from CarnaBiosciences, Inc.; CDK9/CycT1 was purchased from Lifetech; dimethylsulfoxide, ATP, DTT solution were purchased from Sigma-Aldrich; EDTAsolution was purchased from GIBCO; LANCE® Detection Buffer, 10× andLANCE® Ultra Europium-anti-phospho-eIF4E-binding protein 1 (Thr37/46)and LANCE® Ultra ULight™-eIF4E-binding protein 1 (Thr37/46) Peptide werepurchased from Perkinelmer.

Test Procedure:

1. Take 10 mM test compound stock solution, in 96-well compound plate,DMSO was used to make compound with an initial concentration of 100×,then this concentration was used as the first concentration, 3-folddiluted to make 10 serial concentrations; 1 μL each serial dilution wasthen added to 19 μL 1× reaction buffer to prepare 5× compound for use; 2μL 5× compound was transferred from 96-well plate into 384-well plate;compound-free control well was added 2 μL the following liquid: 19 μL 1×reaction buffer with the addition of 1 μL DMSO; 2 μL 250 mM EDTA wasadded to the Min control well.

2.1× reaction buffer was used to formulate the kinase, substrate, andATP into a 2.5× enzyme/substrate mixture and 2.5× ATP solutionrespectively. In the experiment, the final concentration of CDK1/CycBkinase was 3.20 ng/μL, the final concentration of ATP was 12 μM; thefinal concentration of CDKS/p25 kinase was 0.0334 ng/μL, the finalconcentration of ATP was 4 μM; the final concentration of CDK7/CycH/MAT1kinase was 1.93 ng/μL, the final concentration of ATP was 20 μM; thefinal concentration of CDK9/CycT1 kinase was 0.60 ng/μL, the finalconcentration of ATP was 12 μM; added 2.5× enzyme/substrate mixture to a384-well plate, incubated at room temperature for 5 minutes; then added2.5× ATP solution, reacted at room temperature for 30 minutes.

3. LANCE® Detection Buffer was used, 1× to prepare 2× LANCE® UltraEuropium-anti-phospho-eIF4E-binding protein 1 (Thr37/46) for use. Afterthe enzymatic reaction was continued for 30 minutes, 10 mM EDTA wasadded to 384-well plate and reacted at room temperature for 5 minutes.Then LANCE® Ultra Europium-anti-phospho-eIF4E-binding protein 1(Thr37/46) was added, reacted at room temperature for 1 hour.

4,384-well plate was placed in HERAEUS Multifuge X1R centrifuge,centrifuged at 2000 rpm for 2 minutes; data was measured on EnVision™,337 nM wavelength laser was selected as the excitation light, measuredat RFU665 nM and RFU615 nM, and RFU665 nM/RFU615 nM×10000 was used asthe final data for analysis.

5. Graphpad Prism 5.0 was used to perform Log (inhibitor) vs.response-Variable slope (four parameters) curve fitting on the data andthe corresponding IC₅₀ (half maximal inhibitory concentration)wascalculated.

The test results were shown in Table 12.

TABLE 12 Activity test result at kinase level Compound CDK1 CDK5 CDK7CDK9 number IC₅₀, nM IC₅₀, nM IC₅₀, nM IC₅₀, nM LY2835219 263.2/557.9081.80/51.80 667.10/225.90 34.55/49.28 I-5 97.25 913.41 13.04 I-8 73.16393.28 11.43 I-9 62.25 13156.54 7.52 I-22 183.44 1044.56 36.09 I-2344.80 801.32 8.21 I-24 61.16 2892.62 8.51 I-25 86.66 978.09 10.54 I-29222.26 573.79 48.04 I-38 26.21 >30000 0.92 I-46 177.50 1280.02 82.04I-47 491.11 563.30 104.66 I-50 726.02 718.19 89.84 I-51 119.19 1153.1065.83 I-52 368.21 91.52 223.30 332.39 I-54 357.21 1817.51 80.43 I-59583.83 650.34 152.40 I-60 306.33 1194.59 82.12 I-61 347.63 710.25 61.45I-62 69.04 2818.63 2.44 I-63 143.40 33.57 261.10 30.28 I-65 360.011076.14 88.95 I-67 232.37 555.53 26.64 I-68 87.81 41.00 20.47 6.94 I-69138.80 11.44 129.20 16.22 I-70 3614.00 620.20 196.40 316.20 I-74 911.9036.99 104.00 211.50 I-79 209.00 82.39 279.80 47.45 I-80 1096.00 91.22146.60 223.30 I-82 125.5 22.56 11.40 4.97 I-83 171.9 28.99 38.13 12.51I-84 107.8 42.32 16.70 6.58 I-86 101.9 15.35 60.97 10.68 I-88 283.533.29 95.93 27.99 I-90 218.2 40.30 36.48 22.75 I-92 87.39 27.99 50.137.47 I-93 199.4 139.60 147.00 13.98 I-94 264.1 67.33 66.25 13.53 I-981702.0 288.30 669.70 126.9 I-101 78.94 3.90 56.98 6.74 I-109 164.7 47.2499.42 7.03 I-111 55.07 15.92 104.8 5.44 I-114 161.2 14.61 195.3 15.32I-126 291.56 1181.63 47.08 I-127 997.52 779.46 145.43 I-129 132.9 55.2753.40 10.99 I-130 207.9 85.75 109.10 20.79 I-131 1054 238.60 124.10163.70 I-142 1233 29.33 314.7 133.1 I-154 442.6 15.57 180.8 20.72 I-157273.1 21.36 214.6 23.56 I-176 134.6 8.37 148.7 10.54 I-202 141.3 7.17159.5 8.42 I-203 546.6 28.46 250.1 42.29 comparative 50.78 325.62 9.21example A comparative 41.12 5366.87 9.18 example B comparative 131.931094.50 14.77 example C comparative 83.36 799.36 10.80 example E

It is to be understood that the foregoing description of the preferredembodiments is intended to be purely illustrative of the principles ofthe invention, rather than exhaustive thereof, and that changes andvariations will be apparent to those skilled in the art, and that thepresent invention is not intended to be limited other than expressly setforth in the following claims.

What is claimed is:
 1. A compound represented by formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;wherein, m is 1; n is 0; p is 1; q is 1; X is N; Y is CH; R¹ is halogen;R² is C₁-C₂₀ alkyl; R³ is hydrogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀alkynyl, C₃-C₁₂ cycloalkyl, or C₁-C₉ heterocycloalkyl; wherein the“heterocycloalkyl” connects to another group via the carbon atomthereof, the heteroatom in the heterocycloalkyl is selected from thegroup consisting of O, N and S, the number of the heteroatom is 1 to 3;wherein, the C₁-C₂₀ alkyl, the C₂-C₂₀ alkenyl, the C₂-C₂₀ alkynyl, theC₃-C₁₂ cycloalkyl and the C₁-C₉ heterocycloalkyl are independentlyoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, oxo, mercapto,cyano, amino, nitro, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,C₁-C₂₀ alkoxy, C₁-C₂₀ alkylthio, C₃-C₁₂ cycloalkyl, NH(C₁-C₂₀ alkyl) andN(C₁-C₂₀ alkyl)₂; R⁴ is halogen; R⁵ is C₁-C₂₀ alkyl substituted with

R^(11a) and R^(11b) are independently hydrogen, C₁-C₂₀ alkyl, C₂-C₂₀alkenyl, C₂-C₂₀ alkynyl, C₃-C₁₂ cycloalkyl or C₁-C₉ heterocycloalkyl;wherein the C₁-C₂₀ alkyl, the C₂-C₂₀ alkenyl, the C₂-C₂₀ alkynyl, C₃-C₁₂cycloalkyl and C₁-C₉ heterocycloalkyl are independently optionallysubstituted with one or more substituent independently selected from thegroup consisting of C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl,hydroxy, nitro, carboxyl, formyl, mercapto, C₁-C₂₀ silyl, halogen,

trifluoromethyl, cyano, C₁-C₂₀ alkoxy, C₃-C₁₂ cycloalkyl, C₁-C₉heterocycloalkyl, C₆-C₁₂ aryl, C₁-C₉ heteroaryl,

and —SF₅; or, R^(11a) and R^(11b) together with the nitrogen atom towhich they are attached, form a moiety selected from the groupconsisting of

t and u are independently 1, 2 or 3; R^(c) is C(R^(cs))₂, NR^(cs), O, S,Si(R^(cs))₂ or Se; each R^(cs) is independently H, C₁-C₆ alkyl, orB(OH)₂; v and w are independently 1, 2 or 3; R^(ch) is CH or PH₂; R^(cx)is CH₂, O, S, or ═N—OH; R^(hc) is H or C₁-C₆ alkyl; v1 and w1 areindependently 1, 2 or 3; R^(c1) and R^(c2) are independently O, NH orN—CN; each R²⁰ is independently hydrogen, C₁-C₂₀ alkyl, hydroxy, C₁-C₂₀alkoxy or

each R²¹ is independently halogen, C₁-C₂₀ alkyl, hydroxy, C₁-C₂₀ alkoxyor

each R²² is independently hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀alkyl; R^(23a) is hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl;R^(23b) is hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; R^(24a) ishydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; R^(24b) is hydrogen,hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; each R^(25a) is independentlyhydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; each R^(25b) isindependently hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; R²⁶ isC₁-C₂₀ alkyl; R^(27a) is hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀alkyl; R^(27b) is hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀ alkyl; eachR^(29a) is independently hydrogen, hydroxy, C₁-C₂₀ alkoxy or C₁-C₂₀alkyl; each R^(29b) is independently hydrogen, hydroxy, C₁-C₂₀ alkoxy orC₁-C₂₀ alkyl; R^(6a) is hydrogen or C₁-C₂₀ alkyl; R^(6b) is hydrogen orC₁-C₂₀ alkyl; R^(6c) is hydrogen or C₁-C₂₀ alkyl; R^(6d) is hydrogen orC₁-C₂₀ alkyl; wherein each heterocycloalkyl and heteroaryl independentlycontains 1, 2, 3, 4, 5, 6 or 7 heteroatom independently selected fromthe group consisting of O, N, P, S, Se, B and Si.
 2. The compoundaccording to claim 1 or a pharmaceutically acceptable salt, stereoisomeror tautomer thereof, wherein the C₂-C₂₀ alkenyl is independently C₂-C₁₂alkenyl; and/or, the C₂-C₂₀ alkynyl is independently C₂-C₁₂ alkynyl;and/or, the C₁-C₂₀ alkyl in the definition of C₁-C₂₀ alkyl, NH(C₁-C₂₀alkyl) and N(C₁-C₂₀ alkyl)₂ is independently C₁-C₁₂ alkyl; and/or, theC₁-C₂₀ alkylthio is C₁-C₁₂ alkylthio; and/or, the C₁-C₂₀ alkoxy isindependently C₁-C₁₂ alkoxy; and/or, the C₁-C₂₀ silyl is C₁-C₁₂ silyl;and/or, the C₃-C₁₂ cycloalkyl is independently C₃-C₈ cycloalkyl; and/or,the C₁-C₉ heterocycloalkyl is independently C₃-C₈ heterocycloalkylhaving 1, 2, 3 or 4 heteroatom independently selected from the groupconsisting of O, N, P, S, Se, B and Si; and/or, the C₁-C₉ heteroaryl isC₁-C₆ heteroaryl; and/or, the C₆-C₁₂ aryl is C₆-C₁₀ aryl.
 3. Thecompound according to claim 1, or a pharmaceutically acceptable salt,stereoisomer or tautomer thereof, wherein the C₂-C₂₀ alkenyl isindependently C₂-C₆ alkenyl; and/or, the C₂-C₂₀ alkynyl is independentlyC₂-C₆ alkynyl; and/or, the C₁-C₂₀ alkyl in the definition of C₁-C₂₀alkyl, NH(C₁-C₂₀ alkyl) and N(C₁-C₂₀ alkyl)₂ is independently C₁-C₆alkyl; and/or, the C₁-C₂₀ alkylthio is C₁-C₆ alkylthio; and/or, theC₁-C₂₀ alkoxy is independently C₁-C₆ alkoxy; and/or, the C₁-C₂₀ silyl isC₁-C₆ silyl; and/or, the C₃-C₁₂ cycloalkyl is independently C₃-C₆cycloalkyl; and/or, the C₁-C₉ heterocycloalkyl is independently C₃-C₅heterocycloalkyl having 1, 2, 3 or 4 heteroatom independently selectedfrom the group consisting of O, N, P, S, Se, B and Si; and/or, the C₁-C₉heteroaryl is C₁-C₆ heteroaryl having 1, 2, 3 or 4 heteroatomindependently selected from the group consisting of O, N, P, S, Se, Band Si.
 4. The compound according to claim 1 or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof, wherein R¹ isfluorine; and/or, R² is methyl; and/or, when R³ is optionallysubstituted C₁-C₂₀ alkyl, the optionally substituted C₁-C₂₀ alkyl ismethyl, ethyl, isopropyl, tert-butyl, 1-ethylpropyl, 1-cyclopropylethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,1-methyl-2,2,2-trifluoroethyl or cyclopropylmethyl; and/or, when R³ isoptionally substituted C₃-C₁₂ cycloalkyl, the optionally substitutedC₃-C₁₂ cycloalkyl is 1-methylcyclopropyl, cyclopropyl, 3-oxocyclobutyl3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl,cyclobutyl, cyclopentyl, cyclohexyl or

and/or, when R³ is optionally substituted C₁-C₉ heterocycloalkyl, theoptionally substituted C₁-C₉ heterocycloalkyl is 3-oxetanyl or3-methyl-3-azacyclobutyl; and/or, R⁴ is fluorine; and/or, when R^(11a)and R^(11b) are independently optionally substituted C₁-C₂₀ alkyl, theoptionally substituted C₁-C₂₀ alkyl is independently —CF₃, hydroxyethyl,2-dimethylaminoethyl; and/or, when R^(11a) and R^(11b) are independentlyoptionally substituted C₂-C₂₀ alkenyl, the optionally substituted C₂-C₂₀alkenyl is independently 2-propenyl; and/or, when R^(11a) and R^(11b)are independently optionally substituted C₂-C₂₀ alkynyl, the optionallysubstituted C₂-C₂₀ alkynyl is independently 2-propynyl; and/or, whenR^(11a) and R^(11b) are independently optionally substituted C₁-C₉heterocycloalkyl, the optionally substituted C₁-C₉ heterocycloalkyl isindependently

and/or, when R^(cs) is C₁-C₆ alkyl, the C₁-C₆ alkyl is methyl, ethyl,propyl or isopropyl; and/or, when R^(hc) is C₁-C₆ alkyl, the C₁-C₆ alkylis methyl, ethyl or propyl; and/or, when R^(27a) and R^(27b) areindependently optionally substituted C₁-C₂₀ alkyl, the optionallysubstituted C₁-C₂₀ alkyl is independently methyl, ethyl or propyl;and/or, R^(6a) is hydrogen; and/or, R^(6b) is hydrogen; and/or, R^(6c)is hydrogen; and/or, R^(6d) is hydrogen.
 5. The compound according toclaim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof, wherein R⁵ is C₁-C₆ alkyl substituted with


6. The compound according to claim 1 or a pharmaceutically acceptablesalt, stereoisomer or tautomer thereof wherein R⁵ is ethyl substitutedwith


7. The compound according to claim 1 or a pharmaceutically acceptablesalt, stereoisomer or tautomer thereof, wherein R^(11a) and R^(11b) areindependently hydrogen or C₁-C₆ alkyl.
 8. The compound according toclaim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof, wherein the compound is selected from the group consisting of


9. A method for inhibiting tumor cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the compound according to claim 1 or a pharmaceuticallyacceptable salt, stereoisomer or tautomer thereof.
 10. The methodaccording to claim 9, wherein the tumor is selected from the groupconsisting of breast cancer, colon cancer, non-small cell carcinoma,brain astrocytoma, chronic myelogenous leukemia, pancreatic cancer,acute monocytic leukemia, hepatocellular carcinoma, liveradenocarcinoma, gastric carcinoma, non-small cell lung cancer, malignantglioblastoma and prostate adenocarcinoma.
 11. A method for treating atumor in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the compound according toclaim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof.
 12. The method according to claim 11, wherein the tumor isselected from the group consisting of breast cancer, colon cancer,non-small cell carcinoma, brain astrocytoma, chronic myelogenousleukemia, pancreatic cancer, acute monocytic leukemia, hepatocellularcarcinoma, liver adenocarcinoma, gastric carcinoma, non-small cell lungcancer, malignant glioblastoma and prostate adenocarcinoma.
 13. A methodfor inhibiting cyclin-dependent kinase activity in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of the compound according to claim 1 or apharmaceutically acceptable salt, stereoisomer or tautomer thereof. 14.A pharmaceutical composition comprising the compound according to claim1 or a pharmaceutically acceptable salt, stereoisomer or tautomerthereof, and at least one pharmaceutically acceptable excipient.